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DOI: 10.1055/s-0035-1560390
Highly Stereoselective Synthesis of Fluoroalkene Dipeptides via the Novel Chromium(II)-Mediated Carbon–Fluorine Bond Cleavage/New Carbon–Carbon Bond Formation
Publication History
Received: 02 October 2015
Accepted after revision: 20 November 2015
Publication Date:
29 December 2015 (online)
Abstract
An efficient chromium(II)-mediated reductive coupling reaction of various CBrF2-containing molecules and aldehydes has been developed. This reaction proceeds presumably via the monofluorinated dichromium(III) intermediate generated by the carbon–fluorine bond activation, and provides a general and straightforward access to synthesize a variety of (E)- or (Z)-β-fluoroallylic alcohols in a highly stereoselective manner. Based on the novel reductive coupling, four types of fluoroalkene dipeptide analogues could be stereoselectively prepared.
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Key words
β-fluoroallylic alcohol derivatives - carbon–fluorine bond activation - chromium(II) chloride - stereoselective - fluoroalkene bioisosteresFluoroalkenes have been well recognized as among the most important and valuable peptide bond bioisosteres because the fluoroalkene and the peptide bond frameworks are closely similar in the structural and electronic properties. More specifically, an amide bond in bioactive peptides is sometimes easily hydrolyzed by an enzyme in vivo, resulting in the inactivation of the peptide, but due to hydrolytic stability of the fluoroalkene framework, peptidomimetics, in which the amide bond is replaced with the fluoroalkene unit, maintain the original bioactivity and often simultaneously provoke very interesting additional biological activities.[1] For this reason, a large number of synthetic methods, such as electrophilic fluorination of various vinylmetal species,[2] Horner–Wadsworth–Emmons reaction of monofluorinated phosphonate with aldehydes,[3] SN2′ reaction of α,α-difluoroallylic compounds with organocopper reagents,[4] and others,[5] have been developed for the incorporation of a fluoroalkene skeleton into a wide range of bioactive peptides. Although such synthetic procedures absolutely play an important role in synthesizing a variety of stereochemically defined fluoroalkenes, they also have various drawbacks, like difficulties on the preparation of the substrates, narrow range of applicable substrates, etc. As a consequence, it has still been a very important subject to explore a new methodology for constructing fluoroalkene frameworks stereoselectively.
Carbon–fluorine (C–F) bond has a very large bond energy and has been known as the most chemically stable bond. Accordingly, reactions that efficiently cleave this C–F bond and subsequently create a new carbon–carbon (C–C) bond are significantly attractive from the viewpoint of a new synthetic methodology. In recent years, such carbon elongations have come under the spotlight.[6]
In this article, we describe a highly stereoselective synthesis of various (E)- or (Z)-β-fluoroallylic alcohols based on C–F bond cleavage of CBrF2-containing molecules in the presence of the early transition metal, chromium(II)[7] followed by the addition reaction of the resultant α-fluorovinyl chromium species with various aldehydes in detail.[8] Additionally, we also report the stereoselective synthesis of various fluoroalkene dipeptides through the above Cr(II)-mediated reductive coupling reaction.
Scope and Limitations
For this investigation, we first selected several CBrF2-containing substrates, such as the imide 1,[9] the esters 2 [10] and 4,[11] the silyl ethers 3 and 5,[10] and also the alkane 6.[12] These substrates were easily prepared as shown in Scheme [1]. Treatment of 3,3,3-trifluoropropanoyloxazolidinone with 1.5 equivalents each of TMSOTf and Et3N in CH2Cl2 at 0 °C for 0.5 hour afforded the corresponding silyl enol ether, which was subsequently subjected to 2.0 equivalents of TiBr4 in CH2Cl2 at –20 °C for 2 hours, leading to 3-(3-bromo-3,3-difluoropropanoyl)-2-oxazolidinone (1) in 75% isolated yield over two steps. The radical addition of CBr2F2 toward ethyl vinyl ether in the presence of NaHCO3 and Na2S2O4 in EtOH at the reflux temperature for 2 hours, followed by treating the resultant reaction mixture with an excess amount of Caro’s acid for 24 hours, gave ethyl 3-bromo-3,3- difluoropropionate (2) in 36% combined yield. This ester 2 was reduced with 2.3 equivalents of DIBAL-H to provide the corresponding alcohol, which was subjected to 2.0 equivalents each of TBDPSCl and imidazole in THF for 20 hours to afford the desired 1-bromo-3-(tert-butyldiphenylsilyloxy)-1,1-difluoropropane (3) in 49% yield over two steps. The radical addition of CBr2F2 toward ethyl acrylate in the presence of Zn and CuBr in Et2O also proceeded to give the corresponding ethyl 4-bromo-4,4-difluorobutyrate (4) in an acceptable yield, which could be converted to 1-bromo-4-(tert-butyldiphenylsilyloxy)-1,1-difluorobutane (5) by the similar procedure used to prepare compound 3. Finally, the radical adduct, which could be readily prepared through the reaction of CBr2F2 with oct-1-ene in the presence of CuCl (0.01 equiv) and 2-aminoethanol (0.5 equiv) in tert-BuOH at 85 °C for 48 hours, was treated with 2.0 equivalents of NaBH4 in DMSO at 70 °C for 6 hours to afford 1-bromo-1,1-difluorononane (6) in 38% yield.
With various substrates 1–6 in hand, the reaction of 1 with benzaldehyde in the presence of CrCl2 was first examined as shown in Table [1]. On treating 1 with 2.0 equivalents of benzaldehyde in the presence of 3.0 equivalents of CrCl2 and a catalytic amount of LiI (0.2 equiv) in DMF at –20 °C for 4 hours, the corresponding β-fluoroallylic alcohol 7a was obtained in only 15% yield (Table [1], entry 1). Longer reaction time was not effective to increase the yield (entry 2). In each case, the starting material 1 was completely consumed. The yield of 7a was greatly improved from 18% to 84–86% when the reaction was carried out at 0 °C to room temperature (entries 3 and 4), though higher temperature such as 60 °C rather decreased the yield (entry 5). Using only 2.0 equivalents of CrCl2 brought about a significant drop in the yield (entry 6). The yield somewhat decreased even when only 1.2 equiv of benzaldehyde was used or LiI was not used[13] (entries 7 and 8). Finally, the use of 4.0 equiv of CrCl2 led to the best reaction yield (entry 9). In all cases, only the E-isomer was obtained.[14]
a Determined by 19F NMR spectroscopy. Value in parentheses is of isolated yield.
b In all cases, (E)-7a was obtained as the sole isomer.
c Only 2.0 equiv of CrCl2 was used.
d Only 1.2 equiv of PhCHO was used.
e Without LiI.
f Four equiv of CrCl2 was used.
Upon optimization of the reaction conditions (Table [1], entry 9), a series of aldehydes were tested by using 1 to explore the generality of this Cr(II)-mediated reductive coupling reactions. The results are summarized in Table [2].
a Reaction conditions: 1 (0.5 mmol), R1CHO (1.0 mmol), CrCl2 (2.0 mmol), LiI (0.1 mmol), DMF (1.5 mL) at 0 °C for 4 h under argon.
b Determined by 19F NMR spectroscopy.
c Values in parentheses are of isolated yield.
The reaction with aromatic aldehydes bearing an electron-donating group (Me, MeO; Table [2], entries 2 and 3) or an electron-withdrawing group (F substituent, entry 4) at the para position of the benzene ring proceeded efficiently to give the corresponding β-fluoroallylic alcohols 7b–d in good to high yields. Various aliphatic aldehydes, such as butyraldehyde (entry 6) and isobutyraldehyde (entry 7), also showed satisfactory results. Notably, even much bulkier pivalaldehyde provided the corresponding adduct 7h in a high yield (entry 8). Disappointingly, a strongly electron-withdrawing group, like a CF3 group, on the benzene ring hampered the desired reaction proceeding (entry 5). In addition, α,β-unsaturated aldehyde, like crotonaldehyde, resulted in a significant decrease of the yield (entry 9). In all cases, only (E)-β-fluoroallylic alcohols were observed and no Z-isomer was detected.
Next, our attention was directed toward the Cr(II)-mediated reaction of 1-bromo-3-(tert-butyldiphenylsilyloxy)-1,1-difluoropropane (3) with various aldehydes under the same reaction conditions as employed in Table [2]. The results are collected in Table [3].
First of all, the desired β-fluoroallylic alcohol 8a was obtained in only 44% yield under the reaction conditions employed for the reaction of 1 (Table [3], entry 1). In this case, 40% of the starting material 3 still remained unreacted. Therefore, the amounts of CrCl2 and LiI were increased from 4.0 to 6.0 equivalents and from 0.2 to 0.5 equivalent, respectively. As a result, the starting material 3 was completely consumed and the corresponding β-fluoroallylic alcohol 8a was obtained in 68% yield (entry 2). Surprisingly, only the Z-isomer was obtained[14] and no trace of E-isomer was detected. The reactions with various aromatic aldehydes, such as p-tolualdehyde, p-anisaldehyde, and 4-fluorobenzaldehyde, also took place smoothly to give the corresponding adducts in an exclusive Z-selective manner (entries 3, 4, and 5). Similarly, various aliphatic aldehydes, such as butyraldehyde, isobutyraldehyde, and pivalaldehyde, also gave the corresponding β-fluoroallylic alcohol derivatives with high Z-selectivity in high yields (entries 7–9). As observed in the Cr(II)-mediated reductive coupling of 1, both 4-trifluoromethylbenzaldehyde and crotonaldehyde gave poor yields (entries 6 and 10).
a Reaction conditions: 3 (0.3 mmol), aldehyde (0.6 mmol), CrCl2 (1.8 mmol), LiI (0.15 mmol), DMF (1.2 mL) at r.t. for 4 h under argon.
b Determined by 19F NMR spectroscopy.
c Values in parentheses are of isolated yield.
d Reaction conditions: 3 (0.3 mmol), aldehyde (0.6 mmol), CrCl2 (1.2 mmol), LiI (0.06 mmol), DMF (1.2 mL) at 0 °C for 4 h under argon.
e The starting material 3 was recovered in 40% yield.
In an analogous way, ethyl 3-bromo-3,3-difluoropropionate (2), ethyl 4-bromo-4,4-difluorobutyrate (4), 1-bromo-4-(tert-butyldiphenylsilyloxy)-1,1-difluorobutane (5), and 1-bromo-1,1-difluorononane (6) were also subjected to the same reaction conditions as used in Table [3]. The results are listed in Table [4].
a Reaction conditions: 2 and 4–6 (0.3 mmol), aldehyde (0.6 mmol), CrCl2 (1.8 mmol), LiI (0.15 mmol), DMF (1.2 mL) at r.t. for 4 h under Ar atmosphere.
b Determined by 19F NMR spectroscopy.
c Values in parentheses are of isolated yield.
d Ethyl β,β-difluoroacrylate (13) was obtained in 18% yield.
e The starting material 4 was recovered in 47% yield.
f Not determined.
g The diastereomeric ratio was at 45:55 (entry 16) and at 62:38 (entry 18).
h The starting material 6 was recovered in 44% yield.
i The starting material was recovered in 7% yield.
The reaction of 2 with benzaldehyde did not give any desired coupling product 9a, and ethyl β,β-difluoroacrylate (13) was obtained in only 18% yield (Figure [1]).[15] On the other hand, the ester 4, in which the carbon framework has one carbon extension from 2, underwent a smooth reductive coupling with benzaldehyde to give the corresponding adduct 10a in 76% yield. Furthermore, various aromatic as well as aliphatic aldehydes could participate well in the reductive coupling reaction to afford the corresponding adducts 10b–d,f–h in acceptable yields. As observed in the reaction of 1 and 3, however, neither 4-trifluoromethylbenzaldehyde nor crotonaldehyde afforded the desired products 10e and 10i in good yields.
In the same way, the other starting materials 5 and 6 could be also successfully applied for the reductive coupling reaction with various aldehydes, except for 4-trifluoromethylbenzaldehyde and crotonaldehyde, with various β-fluoroallylic alcohols 11a,c,g,h,j–m, and 12a–d,f–h being obtained in high to excellent yields. In all cases, a high Z-stereoselection was observed.
With the highly selective preparation of fluoroalkenes in hand, the investigation was next shifted to their synthetic application. As mentioned previously, fluoroalkene is one of the important bioisosteres found occasionally in medicinal chemistry (Figure [2]).
To prove our concept, (Z)-fluoroalkene 11 was chosen as the ideal starting material.[16] First, alcohol moiety was reacted with sodium azide to afford β-fluoroallylic azides as a regioisomeric mixture of 14 and 15, which were generated through an SN2 and SN2′ reaction pathway, respectively[5j] [17] (Table [2]). Regioselectivity was highly dependent on the substrates. If R1 is aromatic, compound 15 is the major product, if R1 is aliphatic, the major product is the desired product 14, and interestingly, when R1 is CH2OPMB, only the SN2 type of product 14 was observed. The products 14 and 15 were unable to separate by the standard condition of silica gel chromatography, therefore the following reduction step was conducted with a mixture of starting materials. However, fortunately, their amine products after reduction were easily separated and used for further chemical transformation (Table [5]). Next, after protection of amine moiety by Boc, the desilylation was conducted smoothly, and Jones oxidation, followed by esterification with diazomethane, gave the desired fluoroalkene bioisosteres of Boc-protected glycine dipeptide analogues (Scheme [2]).
a Isolated yield.
b Values in parentheses are the ratio of regioisomer determined by 19F NMR spectroscopy.
c The diastereomeric ratio was 50:50.
d The diastereomeric ratios of 16 and 17 were 48:52 and 49:51, respectively.
e The diastereomeric ratios of 14 and 15 were 30:70 and 31:69, respectively.
f Isolation of the product was not possible. The yield was determined by 19F NMR spectroscopy.
g The diastereomeric ratios of 16 and 17 were 27:73 and 27:73, respectively.
Based on our experimental results, the reaction mechanism can be proposed as follows (Scheme [3]). Thus, the starting CBrF2-containing substrates can be converted into the corresponding difluorinated chromium species Int-1 via the single electron-transfer mechanism. In Int-1, the C–F bond may be a little bit longer than that in the starting CBrF2-containing substrates due to the nature of a carbenoid. Therefore, the C–F bond activation by CrCl2 presumably takes place to provide the corresponding dichromium species Int-2.
When 1 was employed as the substrate, the Lewis acidic chromium metal can coordinate with the carbonyl oxygen of the oxazolidinone moiety in Int-2 to form a stable seven-membered intermediate. Additionally, this intermediate is more stabilized because the dipole moment vectors on each carbonyl group facing the opposite direction cancel each other. Then, syn-elimination of CrHCl2 takes place to afford the corresponding (Z)-fluorovinyl chromium reagent (Z)-Int-3,[18] which can react with aldehydes to produce the corresponding (E)-β-fluoroallylic alcohols 7.
In the case of 3–6, which do not have any functionality capable of coordinating with the chromium metal, β-elimination of CrHCl2 from the most stable conformer, in which R2 and CrCl2 substituents are located in the antiperiplaner position, avoiding a large steric repulsion, occurs in a syn-fashion, resulting in the formation of a thermodynamically stable (E)-fluorovinyl chromium reagents (E)-Int-3, which can react with various aldehydes to yield the corresponding (Z)-β-fluoroallylic alcohols 8 and 10–12.
In the reaction of 1, β-elimination of HF from Int-1 by the chromium alkoxide Int-4 may also be possible due to a highly acidic α-proton of the carbonyl (Scheme [4]). In this case, Int-1 can be directly converted into (Z)-Int-3, bypassing the formation of the dichromium species Int-2.
Given that the reaction of 1 with benzaldehyde in the presence of only 3.0 equivalents of CrCl2 proceeded efficiently, this β-elimination may play an important role in the Cr(II)-mediated reductive coupling. In fact, some of the steps of this new reaction mechanism depicted in Scheme [3] conflicts with the one described in our previous paper,[8] thus the difluoroalkene could be possibly formed after β-elimination from Int-1, which was initially thought as the key intermediate transformed to fluorovinylchromium species (Z)- or (E)-Int-3 via single electron transfer. In fact, according to the control reaction described in Scheme [5], treating difluoroalkene 20 [19] with benzaldehyde under the standard reaction condition did not give the corresponding desired product 12a with almost quantitative recovery of starting material 20. This fact strongly indicates that the reaction does not proceed via a 1,1-difluoroalkene intermediate.
In summary, we have investigated the highly stereoselective synthesis of (E)- or (Z)-β-fluoroallylic alcohol derivatives based on CrCl2-mediated C–F bond activation reaction. As a result, the substrate 1 having a Lewis basic group, like an oxazolidinone substituent, afforded E-isomers in a highly stereoselective manner, while substrates 3–6 without a Lewis basic substituent gave the Z-isomers stereoselectively. It was proposed that this stereoselection was derived from the interaction of chromium metal and a carbonyl oxygen in the dichromium intermediates. In addition, the novel Cr(II)-mediated reductive coupling reaction could be successfully applied to the stereoselective synthesis of fluoroalkene dipeptide analogues.
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IR spectra were recorded as a liquid film between NaCl plates or KBr disk method for solids with a JASCO FT/IR-4100 type A spectrometer. 1H and 13C NMR spectra were recorded on a JEOL JNM-AL 400 NMR spectrometer in CDCl3 solution with TMS as an internal reference. A JEOL JNM-AL 400 NMR spectrometer was used for determining the yield of the products with C6F6. 19F NMR (376.05 MHz) spectra were recorded on a JEOL JNM-AL 400 NMR spectrometer in CDCl3 solution with CFCl3 as an internal standard. High-resolution mass spectra (HRMS) were recorded on a JEOL JMS-700MS spectrometer by electron impact (EI), chemical ionization (CI), and fast atom bombardment (FAB) methods.
All reactions were routinely monitored by 19F NMR spectroscopy or TLC, and carried out under an atmosphere of argon. EtOH was fleshly distilled from Mg. DMF were freshly distilled from CaH2. All chemicals were of reagent grade and, if necessary, were purified in the usual manner prior to use. TLC was done with Merck silica gel 60 F254 plates, and column chromatography was carried out with Wako gel C-200.
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1-Bromo-3-(tert-butyldiphenylsilyloxy)-1,1-difluoropropane (3); Typical Procedure
Under an argon atmosphere, a solution of ethyl 3-bromo-3,3-difluoropropanoate (2; 0.65 g, 3.0 mmol) in CH2Cl2 was added dropwise to DIBAL-H (6.9 mmol) at –78 °C. The reaction mixture was stirred at that temperature for 2 h and then stirred at 0 °C for 3 h. The reaction was quenched with aq 10% HCl and the mixture was extracted with CH2Cl2 (3 ×). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduce pressure. The resulting residue was used in the next step without further purification. A mixture of the above crude alcohol, t-BuPh2SiCl (1.65 g, 6.0 mmol), and imidazole (0.41 g, 6.0 mmol) in THF (6 mL) was stirred at r.t. for 20 h. Addition of H2O followed by extractive workup and purification by silica gel column chromatography (hexane–EtOAc, 80:1) afforded the desired product; yield: 0.60 g (49%, 1.46 mmol) over two steps; colorless oil.
IR (neat): 3072, 3000, 2932, 2858, 1960, 1590, 1472, 1428, 1362, 1283, 1188, 1114, 998, 880, 823, 702, 613 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.07 (9 H, s), 2.63–2.69 (2 H, tt, J = 6.59, 13.35 Hz), 3.93 (2 H, t, J = 6.59 Hz), 7.39–7.46 (6 H, m), 7.67–7.69 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 26.7, 46.7 (t, J = 20.7 Hz), 58.8 (t, J = 4.1 Hz), 121.2 (t, J = 305.4 Hz), 127.8, 129.8, 133.1, 135.5.
19F NMR (376 MHz, CDCl3): δ = –42.39 (2 F, t, J = 13.35 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C19H24BrF2OSi: 413.0748; found: 413.0751.
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1-Bromo-4-(tert-butyldiphenylsilyloxy)-1,1-difluorobutane (5)
Yield: 3.72 g (69%, 8.70 mmol) over two steps; colorless oil.
IR (neat): 3071, 2932, 2858, 1472, 1428, 1216, 1186, 1112, 1023, 997, 932, 823, 740, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.06 (9 H, s), 1.81–1.88 (2 H, m), 2.45–2.55 (2 H, m), 3.72 (2 H, t, J = 5.99 Hz), 7.38–7.46 (6 H, m), 7.64–7.66 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 26.8, 27.1 (d, J = 2.5 Hz), 41.2 (t, J = 21.5 Hz), 62.0, 123.2 (d, J = 304.5 Hz), 127.7, 129.7, 133.5, 135.5.
19F NMR (376 MHz, CDCl3): δ = –43.76 (2 F, t, J = 14.67 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C20H26BrF2OSi: 427.0904; found: 427.0896.
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1-Bromo-1,1-difluorononane (6)
Under an argon atmosphere, a three-necked, round-bottomed flask equipped with an efficient magnetic stirring bar was charged with CuCl (0.040 g, 0.4 mmol), 2-aminoethanol (1.22 g, 20.0 mmol), t-BuOH (6.6 mL), oct-1-ene (4.49 g, 40 mmol), and CBr2F2 (16.8 g, 80 mmol), and the mixture was stirred at 85 °C for 48 h. Then, all organic materials were filtered through silica gel, which was rinsed with hexanes. The resulting colorless filtrate was concentrated by evaporation and subjected to fractional distillation under reduced pressure, affording 1,3-dibromo-1,1-difluorononane (8.86 g, 27.7 mmol, 69%) as a colorless liquid. Under an argon atmosphere, a three-necked round-bottomed flask equipped with an ice-H2O condenser was charged with 1,3-dibromo-1,1-difluorononane (8.86 g, 27.7 mmol) dissolved in anhydrous DMSO (28 mL). NaBH4 (1.51 g, 40 mmol) was then added in small portions with vigorous stirring over the course of 15 min. After the addition was complete, the bath temperature was raised to 70 °C and the mixture was stirred at this temperature for 6 h. The flask was cooled to r.t., the contents were transferred to an Erlenmeyer flask, and the reaction was quenched with chips of ice. The resulting mixture was carefully acidified with concd HCl, and the aqueous DMSO layer was extracted with Et2O (3 ×). The combined Et2O layers were washed with H2O, dried (Na2SO4), and subjected to fractional distillation under the ambient pressure affording the known compound, 1-bromo-1,1-difluorononane (contaminated with a small amount of 1,1-difluorononane); yield: 1.87 g (38%, 7.7 mmol) as a colorless liquid. The analytical and spectral data were in conformity with the literature.[12]
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E-Selective Chromium(II)-Mediated Reductive Coupling Reaction of 3-(3-Bromo-3,3-difluoropropanoyl)-2-oxazolidinone (1) with Aldehydes; 3-[(E)-3-Fluoro-4-hydroxy-4-phenylbut-2-enoyl]-2-oxazolidinone (7a); Typical Procedure
To a suspension of anhydrous CrCl2 (0.25 g, 2.0 mmol) and LiI (0.013 g, 0.1 mmol) in DMF (1.5 mL) were added benzaldehyde (0.11 g, 1.0 mmol) and imide (0.13 g, 0.5 mmol) at 0 °C. After stirring at that temperature for 4 h, the reaction was quenched with ice-cold H2O. The mixture was extracted with Et2O (3 ×). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (benzene–EtOAc, 3:1) to afford the pure product 7a; yield: 0.11 g (84%, 0.42 mmol); yellow oil.
1H NMR (400 MHz, acetone-d 6): δ = 4.12 (2 H, t, J = 8.03 Hz), 4.48–4.52 (2 H, m), 5.31 (1 H, d, J = 6.00 Hz), 6.47 (1 H, dd, J = 6.00, 27.23 Hz), 7.04 (1 H, d, J = 21.33 Hz), 7.31–7.59 (5 H, m).
13C NMR (100 MHz, acetone-d 6): δ = 43.6, 63,2, 69.0 (d, J = 22.0 Hz), 101.8 (d, J = 30.2 Hz), 127.2, 128.7, 129.1, 140.5 (d, J = 1.3 Hz), 154.4, 164.5 (d, J = 24.7 Hz), 175.4 (d, J = 280.6 Hz).
19F NMR (376 MHz, acetone-d 6): δ = –97.43 (1 F, dd, J = 21.33, 27.23 Hz).
HRMS (FAB+): m/z [M]+ calcd for C13H12FNO4: 265.0750; found: 265.0750.
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3-[(E)-3-Fluoro-4-hydroxy-4-(4-methylphenyl)but-2-enoyl]-2-oxazolidinone (7b)
Yield: 0.089 g (64%, 0.32 mmol); yellow oil.
1H NMR (400 MHz, acetone-d 6): δ = 2.36 (3 H, s), 4.13 (2 H, t, J = 8.06 Hz), 4.48–4.52 (2 H, m), 5.26 (1 H, d, J = 6.11 Hz), 6.47 (1 H, dd, J = 6.11, 27.13 Hz), 7.11 (1 H, d, J = 21.36 Hz), 7.22 (2 H, d, J = 7.97 Hz), 7.51 (2 H, d, J = 7.97 Hz).
13C NMR (100 MHz, acetone-d 6): δ = 21.1, 43.6, 63.1, 69.0 (d, J = 22.1 Hz), 101.6 (d, J = 30.2 Hz), 127.2, 129.7, 137.5, 138.3, 154.4, 164.5 (d, J = 24.7 Hz), 175.6 (d, J = 280.6 Hz).
19F NMR (376 MHz, acetone-d 6): δ = –98.73 (1 F, dd, J = 21.36, 27.13 Hz).
HRMS (FAB+): m/z [M]+ calcd for C14H14FNO4: 279.0907; found: 279.0916.
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3-[(E)-3-Fluoro-4-hydroxy-4-(4-methoxylphenyl)but-2-enoyl]-2-oxazolidinone (7c)
Yield: 0.10 g (69%, 0.35 mmol); yellow oil.
1H NMR (400 MHz, acetone-d 6): δ = 3.79 (3 H, s), 4.11 (2 H, t, J = 8.05 Hz), 4.46–4.51 (2 H, m), 5.18 (1 H, d, J = 6.00 Hz), 6.39 (1 H, dd, J = 6.00, 27.01 Hz), 6.92 (2 H, d, J = 8.58 Hz), 7.04 (1 H, d, J = 21.31 Hz), 7.49 (2 H, d, J = 8.58 Hz).
13C NMR (100 MHz, acetone-d 6): δ = 43.6, 55.5, 63.1, 68.7 (d, J = 22.0 Hz), 101.4 (d, J = 30.2 Hz), 114.5, 128.5, 132.5, 154.4, 160.5, 164.1 (d, J = 24.7 Hz), 175.6 (d, J = 280.6 Hz).
19F NMR (376 MHz, acetone-d 6): δ = –98.67 (1 F, dd, J = 21.31, 27.01 Hz).
HRMS (FAB+): m/z [M]+ calcd for C14H14FNO5: 295.0856; found: 295.0863.
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3-[(E)-3-Fluoro-4-(4-fluorophenyl)-4-hydroxybut-2-enoyl]-2-oxazolidinone (7d)
Yield: 0.13 g (90%, 0.45 mmol); yellow oil.
1H NMR (400 MHz, acetone-d 6): δ = 4.13 (2 H, t, J = 8.17 Hz), 4.47–4.53 (2 H, m), 5.37 (1 H, d, J = 5.84 Hz), 6.46 (1 H, dd, J = 5.84, 27.09 Hz), 7.06 (1 H, d, J = 21.29 Hz), 7.14 (2 H, m), 7.58–7.63 (2 H, m).
13C NMR (100 MHz, acetone-d 6): δ = 43.6, 63.2, 68.3 (d, J = 21.9 Hz), 101.9 (d, J = 29.8 Hz), 115.8 (d, J = 21.6 Hz), 129.2 (d, J = 8.2 Hz), 136.6, 154.4, 163.3 (d, J = 244.4 Hz), 164.5 (d, J = 24.4 Hz), 175.6 (d, J = 280.4 Hz).
19F NMR (376 MHz, acetone-d 6): δ = –115.06 to –114.87 (1 F, m), –98.29 (1 F, dd, J = 21.29, 27.09 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C13H12F2NO4: 284.0734; found: 284.0726.
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3-[(E)-3-Fluoro-4-hydroxyhept-2-enoyl]-2-oxazolidinone (7f)
Yield: 0.079 g (68%, 0.34 mmol); yellow oil.
1H NMR (400 MHz, acetone-d 6): δ = 0.94 (3 H, t, J = 7.38 Hz), 1.35–1.78 (4 H, m), 4.07 (2 H, t, J = 8.05 Hz), 4.43–4.49 (3 H, m), 5.10–5.25 (1 H, m), 6.99 (1 H, d, J = 22.83 Hz).
13C NMR (100 MHz, acetone-d 6): δ = 14.1, 19.3, 36.6, 43.5, 63.1, 67.6 (d, J = 22.9 Hz), 101.3 (d, J = 30.9 Hz), 154.4, 164.2 (d, J = 25.02 Hz), 177.5 (d, J = 280.4 Hz).
19F NMR (376 MHz, acetone-d 6): δ = –97.38 (1 F, dd, J = 22.83, 26.89 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C10H15FNO4: 232.0985; found: 232.0993.
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3-[(E)-3-Fluoro-4-hydroxy-5-methylhex-2-enoyl]-2-oxazolidinone (7g)
Yield: 0.088 g (77%, 0.38 mmol); yellow oil.
1H NMR (400 MHz, acetone-d 6): δ = 0.92 (3 H, d, J = 6.82 Hz), 1.05 (3 H, d, J = 6.66 Hz), 1.91–1.99 (1 H, m), 4.06 (2 H, t, J = 8.03 Hz), 4.48 (2 H, t, J = 8.03 Hz), 4.57 (1 H, d, J = 7.08 Hz), 4.80–4.90 (1 H, m), 7.05 (1 H, d, J = 21.83 Hz).
13C NMR (100 MHz, acetone-d 6): δ = 18.85, 18.86, 32.4, 43.5, 63.0, 73.1 (d, J = 22.5 Hz), 102.2 (d, J = 30.7 Hz), 154.3, 164.4 (d, J = 25.5 Hz), 177.0 (d, J = 280.6 Hz).
19F NMR (376 MHz, acetone-d 6): δ = –95.00 (1 F, dd, J = 21.83, 29.33 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C10H15FNO4: 232.0985; found: 232.0984.
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3-[(E)-3-Fluoro-4-hydroxy-5,5-dimethylhex-2-enoyl]-2-oxazolidinone (7h)
Yield: 0.095 g (77%, 0.39 mmol); yellow oil.
1H NMR (400 MHz, acetone-d 6): δ = 1.00 (9 H, s), 4.07 (2 H, dt, J = 2.11, 8.00 Hz), 4.48 (2 H, t, J = 8.00 Hz), 4.63 (1 H, d, J = 6.93 Hz), 5.04 (1 H, dd, J = 6.93, 30.24 Hz), 7.09 (1 H, d, J = 23.08 Hz).
13C NMR (100 MHz, acetone-d 6): δ = 26.5, 36.3, 43.6, 63.0, 74.4 (d, J = 20.5 Hz), 103.0 (d, J = 31.3 Hz), 154.4, 164.5 (d, J = 25.9 Hz), 176.6 (d, J = 282.8 Hz).
19F NMR (376 MHz, acetone-d 6): δ = –87.58 (1 F, dd, J = 23.08, 30.24 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C11H17FNO4: 246.1142; found: 246.1141.
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Z-Selective Chromium(II)-Mediated Reductive Coupling Reaction of 1-Bromo-3-(tert-butyldiphenylsilyloxy)-1,1-difluoropropane (3) with Aldehydes; (Z)-4-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-phenylbut-2-en-1-ol (8a); Typical Procedure
To a suspension of anhydrous CrCl2 (0.22 g, 1.8 mmol) and LiI (0.020 g, 0.15 mmol) in DMF (1.2 mL) were added benzaldehyde (0.064 g, 0.6 mmol) and the silyl ether 3 (0.12 g, 0.30 mmol) at 0 °C. After stirring at r.t. for 4 h, the reaction was quenched with H2O. The mixture was extracted with Et2O (3 ×). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane–EtOAc, 5:1) to afford the pure product; yield: 0.071 g (56%, 0.17 mmol); yellow oil.
IR (neat): 3392, 3070, 2931, 2858, 1709, 1589, 1494, 1472, 1428, 1262, 1164, 1111, 1060, 885, 740, 701, 612 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.95 (9 H, s), 2.01 (1 H, br s), 4.26 (2 H, dd, J = 2.00, 6.79 Hz), 5.03 (1 H, d, J = 11.91 Hz), 5.09 (1 H, dt, J = 36.72, 6.79 Hz), 7.20–7.34 (11 H, m), 7.56–7.57 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 26.8, 57.1 (d, J = 6.6 Hz), 72.3 (d, J = 32.2 Hz), 107.0, (d, J = 10.7 Hz), 126.7, 127.6, 128.4, 128.5, 129.6, 133.5, 135.5, 139.1, 158.8 (d, J = 260.3 Hz).
19F NMR (376 MHz, CDCl3): δ = –119.05 (1 F, dd, J = 11.91, 36.72 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C26H29FO2SiNa : 443.1819; found: 443.1815.
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(Z)-4-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-(4-methylphenyl)but-2-en-1-ol (8b)
Yield: 0.063 g (48%, 0.14 mmol); yellow oil.
IR (neat): 3395, 3071, 2930, 2858, 1079, 1513, 1472, 1428, 1362, 1163, 1111, 1062, 800, 740, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.05 (9 H, s), 2.31 (1 H, br s), 2.35 (3 H, s), 4.36 (2 H, dd, J = 1.60, 6.49 Hz), 5.09 (1 H, d, J = 11.86 Hz), 5.19 (1 H, dt, J = 36.52, 6.49 Hz), 7.15–7.44 (10 H, m), 7.64–7.70 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 21.2, 26.7, 57.1 (d, J = 6.6 Hz), 72.2 (d, J = 32.2 Hz), 106.9 (d, J = 9.9 Hz), 126.6, 127.6, 129.2, 129.6, 133.6, 135.6, 136.2, 138.2, 158.8 (d, J = 259.5 Hz).
19F NMR (376 MHz, CDCl3) δ = –119.12 (1 F, dd, J = 11.86, 36.52 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C27H31FO2SiNa: 457.1975; found: 457.1972.
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(Z)-4-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-(4-methoxyphenyl)but-2-en-1-ol (8c)
Yield: 0.070 g (52%, 0.16 mmol); yellow oil.
IR (neat): 3419, 3071, 2931, 2857, 1709, 1611, 1512, 1464, 1428, 1250, 1111, 1036, 739, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.04 (9 H, s), 2.00 (1 H, br s), 3.82 (3 H, s), 4.36 (2 H, dd, J = 2.20, 6.59 Hz), 5.09 (1 H, dd, J = 3.20, 10.09 Hz), 5.19 (1 H, dt, J = 36.63, 6.59 Hz), 6.88–6.90 (2 H, m), 7.23–7.44 (8 H, m), 7.63–7.68 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 26.8, 55.3, 57.8 (d, J = 6.6 Hz), 72.0 (d, J = 32.2 Hz), 106.8 (d, J = 11.6 Hz), 113.9, 127.6, 128.1, 129.6, 131.3, 133.6, 135.6, 158.9 (d, J = 259.5 Hz), 159.7.
19F NMR (376 MHz, CDCl3): δ = –118.95 (1 F, dd, J = 10.09, 36.63 Hz).
HRMS (FAB+): m/z [M – H]+ calcd for C27H30FO3Si: 449.1948; found: 449.1938.
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(Z)-4-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-(4-fluorophenyl)but-2-en-1-ol (8d)
Yield: 0.073 g (56%, 0.17 mmol); yellow oil.
IR (neat): 3402, 3071, 2931, 2858, 1709, 1605, 1509, 1472, 1428, 1227, 1111, 1064, 908, 739, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.06 (9 H, s), 2.17 (1 H, br s), 4.37 (2 H, d, J = 6.39 Hz), 5.12 (1 H, d, J = 12.11 Hz), 5.18 (1 H, dt, J = 36.72, 6.39 Hz), 7.03–7.07 (2 H, m), 7.32–7.46 (8 H, m), 7.64–7.72 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 26.8, 57.0 (d, J = 6.6 Hz), 71.7 (d, J = 32.2 Hz), 107.3 (d, J = 11.7 Hz), 115.4 (d, J = 27.8 Hz), 127.6, 128.5 (d, J = 8.2 Hz), 129.7, 133.5, 134.8 (d, J = 2.4 Hz), 135.5, 158.5 (d, J = 258.5 Hz), 162.6 (d, J = 246.2 Hz).
19F NMR (376 MHz, CDCl3): δ = –119.38 (1 F, dd, J = 12.11, 36.72 Hz).
HRMS (FAB+): m/z [M]+ calcd for C26H28F2O2Si: 438.1827; found: 438.1833.
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(Z)-1-(tert-Butyldiphenylsilyloxy)-3-fluorohept-2-en-4-ol (8f)
Yield: 0.066 g (57%, 0.17 mmol); yellow oil.
IR (neat): 3389, 3071, 3050, 2999, 2959, 2932, 2859, 1709, 1589, 1471, 1428, 1305, 1264, 1185, 1112, 939, 852, 822, 740, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.95 (3 H, t, J = 7.39 Hz), 1.07 (9 H, s), 1.26–1.70 (4 H, m), 1.79 (1 H, br s), 4.00–4.07 (1 H, m), 4.37 (2 H, dd, J = 2.20, 6.59 Hz), 5.07 (1 H, dt, J = 37.41, 6.59 Hz), 7.36–7.47 (6 H, m), 7.68–7.73 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 13.8, 18.5, 19.1, 26.8, 35.8, 57.0 (d, J = 7.43 Hz), 70.2 (d, J = 29.8 Hz), 106.1 (d, J = 11.7 Hz), 127.6, 129.6, 133.6, 135.5, 159.8 (d, J = 261.2 Hz).
19F NMR (376 MHz, CDCl3): δ = –122.19 (1 F, dd, J = 15.61, 37.41 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C23H31FO2SiNa: 409.1975; found: 409.1976.
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(Z)-6-(tert-Butyldiphenylsilyloxy)-4-fluoro-2-methylhex-4-en-3-ol (8g)
Yield: 0.069 g (59%, 0.18 mmol); yellow oil.
IR (neat): 3404, 3071, 3050, 2960, 2931, 2858, 1708, 1471, 1428, 1264, 1112, 1059, 1026, 939, 876, 822, 782, 740, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.92 (3 H, d, J = 6.79 Hz), 0.97 (3 H, d, J = 6.79 Hz), 1.07 (9 H, s), 1.69 (1 H, br s), 1.87–1.91 (1 H, m), 3.73 (1 H, dd, J = 6.59, 17.05 Hz), 4.37 (2 H, d, J = 6.49 Hz), 5.07 (1 H, dt, J = 37.12, 6.49 Hz), 7.37–7.46 (6 H, m), 7.69–7.71 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 17.5, 18.8, 19.1, 26.5, 26.8, 57.0 (d, J = 7.4 Hz), 75.8 (d, J = 28.9 Hz), 107.1 (d, J = 11.6 Hz), 127.7, 129.7, 133.7, 135.6, 159.1 (d, J = 261.1 Hz).
19F NMR (376 MHz, CDCl3): δ = –121.25 (1 F, dd, J = 17.05, 37.12 Hz).
HRMS (FAB): m/z [M + Na]+ calcd for C23H31FO2SiNa: 409.1975; found: 409.1976.
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(Z)-6-(tert-Butyldiphenylsilyloxy)-4-fluoro-2,2-dimethylhex-4-en-3-ol (8h)
Yield: 0.076 g (63%, 0.19 mmol); yellow oil.
IR (neat): 3442, 3071, 2957, 2958, 1702, 1671, 1472, 1428, 1264, 1186, 1070, 1014, 937, 822, 788, 740, 612 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.94 (9 H, s), 1.05 (9 H, s), 1.71 (1 H, br s), 3.68 (1 H, d, J = 18.81 Hz), 4.35–4.36 (2 H, m), 5.03 (1 H, dt, J = 37.38, 6.79 Hz), 7.37–7.44 (6 H, m), 7.67–7.71 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 25.8, 26.8, 34.8, 60.0 (d, J = 7.43 Hz), 78.2 (d, J = 27.31 Hz), 107.5 (d, J = 11.7 Hz), 127.7, 129.6, 133.7, 135.5, 159.1 (d, J = 262.0 Hz).
19F NMR (376 MHz, CDCl3): δ = –114.51 (1 F, dd, J = 18.81, 37.38 Hz).
HRMS (FAB+): m/z [M – H]+ calcd for C24H32FO2Si: 399.2156; found: 399.2152.
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Z-Selective Chromium(II)-Mediated Reductive Coupling Reaction of Ethyl 4-Bromo-4,4-difluorobutyrate (4) with Aldehydes; Ethyl (Z)-4-Fluoro-5-hydroxy-5-phenylpent-3-enoate (10a); Typical Procedure
To a suspension of anhydrous CrCl2 (0.22 g, 1.8 mmol) and LiI (0.020 g, 0.15 mmol) in DMF (1.2 mL) were added benzaldehyde (0.064 g, 0.6 mmol) and the ester 4 (0.065 g, 0.3 mmol) at 0 °C. After stirring at r.t. for 4 h, the reaction was quenched with H2O and the mixture was extracted with Et2O (3 ×). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane–EtOAc, 3:1) to afford the pure product; yield: 0.040 g (55%, 0.17 mmol); yellow oil.
IR (neat): 3448, 3032, 2983, 1736, 1495, 1454, 1372, 1266, 1189, 1094, 1060, 1027, 955, 887, 804, 701 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.26 (3 H, t, J = 7.09 Hz), 2.50 (1 H, br s), 3.17 (2 H, d, J = 7.19 Hz), 4.15 (2 H, q, J = 7.09 Hz), 5.22 (1 H, dt, J = 35.26, 7.19 Hz), 5.24 (1 H, d, J = 11.25 Hz), 7.29–7.45 (5 H, m).
13C NMR (100 MHz, CDCl3): δ = 14.1, 29.2 (d, J = 4.9 Hz), 60.9, 72.4 (d, J = 31.4 Hz), 99.5 (d, J = 9.8 Hz), 126.7, 128.4, 128.5, 139.1, 160.4 (d, J = 260.3 Hz), 171.2 (d, J = 2.5 Hz).
19F NMR (376 MHz, CDCl3): δ = –119.34 (1 F, dd, J = 11.25, 35.26 Hz).
HRMS (FAB+): m/z [M]+ calcd for C13H15FO3: 238.1005; found: 238.1009.
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Ethyl (Z)-4-Fluoro-5-hydroxy-5-(4-methylphenyl)pent-3-enoate (10b)
Yield: 0.031 g (40%, 0.12 mmol); yellow oil.
IR (neat): 3438, 2982, 2925, 1737, 1514, 1372, 1264, 1186, 1024, 955, 805, 770, 734 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.26 (3 H, t, J = 7.19 Hz), 1.61 (1 H, br s), 2.35 (3 H, s), 3.17 (2 H, d, J = 6.99 Hz), 4.15 (2 H, q, J = 7.19 Hz), 5.19–5.22 (1 H, m), 5.22 (1 H, dt, J = 35.66, 6.99 Hz), 7.17–7.33 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 14.1, 21.2, 29.2 (d, J = 4.9 Hz), 60.9, 72.3 (d, J = 32.2 Hz), 99.3 (d, J = 12.4 Hz), 126.7, 129.3, 136.2, 138.3, 160.5 (d, J = 259.5 Hz), 171.2 (d, J = 1.7 Hz).
19F NMR (376 MHz, CDCl3): δ = –119.31 (1 F, dd, J = 11.09, 35.66 Hz).
HRMS (FAB+): m/z [M]+ calcd for C14H17FO3: 252.1162; found: 252.1163.
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Ethyl (Z)-4-Fluoro-5-hydroxy-5-(4-methoxyphenyl)pent-3-enoate (10c)
Yield: 0.041 g (51%, 0.15 mmol); yellow oil.
IR (neat): 3449, 2982, 2839, 1736, 1611, 1586, 1513, 1465, 1372, 1304, 1251, 1180, 1113, 1032, 955, 834, 775, 736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.26 (3 H, t, J = 7.49 Hz), 2.63 (1 H, br s), 3.16 (2 H, d, J = 7.19 Hz), 3.80 (3 H, s), 4.14 (2 H, q, J = 7.49 Hz), 5.20 (1 H, dt, J = 36.03, 7.19 Hz), 5.24 (1 H, m), 6.89 (2 H, d, J = 8.59 Hz), 7.35 (2 H, d, J = 8.59 Hz).
13C NMR (100 MHz, CDCl3): δ = 14.1, 29.2 (d, J = 4.9 Hz), 55.3, 60.9, 72.0 (d, J = 31.1 Hz), 99.2 (d, J = 11.7 Hz), 113.9, 128.1, 131.3, 159.7, 160.6 (d, J = 259.5 Hz), 171.2 (d, J = 2.4 Hz).
19F NMR (376 MHz, CDCl3): δ = –119.13 (1 F, dd, J = 9.78, 36.03 Hz).
HRMS (FAB+): m/z [M]+ calcd for C14H17FO4: 268.1111; found: 268.1118.
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Ethyl (Z)-4-Fluoro-5-(4-fluorophenyl)-5-hydroxypent-3-enoate (10d)
Yield: 0.038 g (49%, 0.15 mmol); yellow oil.
IR (neat): 3431, 2985, 1735, 1604, 1509, 1414, 1373, 1225, 1190, 1158, 1098, 1027, 956, 839, 784, 736 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.32 (3 H, t, J = 7.19 Hz), 2.84 (1 H, br s), 3.23 (2 H, d, J = 7.29 Hz), 4.21 (2 H, q, J = 7.19 Hz), 5.27 (1 H, dt, J = 35.26, 7.29 Hz), 5.28 (1 H, d, J = 11.25 Hz), 7.10–7.14 (2 H, m), 7.46–7.49 (2 H, m).
13C NMR (100 MHz, CDCl3): δ = 14.1, 29.1 (d, J = 5.8 Hz), 61.0, 71.7 (d, J = 31.3 Hz), 99.6 (d, J = 11.6 Hz), 115.4, 128.5 (d, J = 8.2 Hz), 134.9 (d, J = 3.3 Hz), 160.3 (d, J = 260.3 Hz), 162.7 (d, J = 246.3 Hz), 171.2 (d, J = 2.5 Hz).
19F NMR (376 MHz, CDCl3): δ = –114.14 to –114.22 (1 F, m), –119.43 (1 F, dd, J = 11.25, 35.26 Hz).
HRMS (FAB+): m/z [M]+ calcd for C13H14F2O3: 256.0911; found: 256.0914.
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Ethyl (Z)-4-Fluoro-5-hydroxyoct-3-enoate (10f)
Yield: 0.026 g (42%, 0.13 mmol); yellow oil.
IR (neat): 3437, 2961, 2874, 1739, 1466, 1372, 1188, 1118, 1028, 953 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.94 (3 H, t, J = 7.39 Hz), 1.26 (3 H, t, J = 6.79 Hz), 1.37–1.46 (2 H, m), 1.60–1.66 (2 H, m), 2.08 (1 H, br s), 3.14 (2 H, d, J = 7.19 Hz), 4.08–4.17 (3 H, m), 5.07 (1 H, dt, J = 36.77, 7.19 Hz).
13C NMR (100 MHz, CDCl3): δ = 13.8, 14.1, 18.5, 29.1 (d, J = 5.8 Hz), 35.8, 60.9, 70.2 (d, J = 28.9 Hz), 98.5 (d, J = 12.3 Hz), 161.4 (d, J = 261.2 Hz), 171.3 (d, J = 2.5 Hz).
19F NMR (376 MHz, CDCl3): δ = –122.41 (1 F, dd, J = 15.79, 36.77 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C10H17FO3Na: 227.1059; found: 227.1062.
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Ethyl (Z)-4-Fluoro-5-hydroxy-6-methylhept-3-enoate (10g)
Yield: 0.033 g (54%, 0.16 mmol); yellow oil.
IR (neat) 3445, 2965, 2875, 1738, 1469, 1371, 1259, 1189, 1123, 1123, 1024, 956, 879, 831 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.95 (3 H, d, J = 6.59 Hz), 0.99 (3 H, d, J = 6.59 Hz), 1.26 (3 H, t, J = 7.09 Hz), 1.78 (1 H, br s), 1.89–1.96 (1 H, m), 3.16 (2 H, dm, J = 7.24 Hz), 3.82 (1 H, dd, J = 6.99, 17.25 Hz), 4.15 (2 H, q, J = 7.09 Hz), 5.07 (1 H, dt, J = 36.58, 7.24 Hz).
13C NMR (100 MHz, CDCl3): δ = 14.1, 17.6, 18.8, 29.1 (d, J = 5.7 Hz), 31.2, 60.9, 75.9 (d, J = 28.1 Hz), 99.4 (d, J = 12.5 Hz), 160.7 (d, J = 261.2 Hz), 171.3 (d, J = 1.6 Hz).
19F NMR (376 MHz, CDCl3): δ = –119.59 (1 F, dd, J = 17.25, 36.58 Hz).
HRMS (FAB+): m/z [M – H]+ calcd for C10H16FO3: 203.1083; found: 203.1088.
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Ethyl (Z)-4-Fluoro-5-hydroxy-6,6-dimethylhept-3-enoate (10h)
Yield: 0.020 g (31%, 0.09 mmol); yellow oil.
IR (neat): 3461, 2958, 2908, 2873, 1793, 1479, 1467, 1370, 1330, 1261, 1188, 1076, 1018, 957, 911, 849, 770 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.97 (9 H, s), 1.26 (3 H, t, J = 7.19 Hz), 1.99 (1 H, br s), 3.15 (2 H, m), 3.78 (1 H, d, J = 19.13 Hz), 4.15 (2 H, q, J = 7.19 Hz), 5.03 (1 H, dt, J = 36.52, 7.29 Hz).
13C NMR (100 MHz, CDCl3): δ = 14.1, 25.8, 29.2 (d, J = 5.7 Hz), 34.9, 60.9, 78.2 (d, J = 28.1 Hz), 100.3 (d, J = 12.5 Hz), 160.7 (d, J = 262.0 Hz), 171.2 (d, J = 1.7 Hz).
19F NMR (376 MHz, CDCl3): δ = –114.92 (1 F, dd, J = 19.13, 36.52 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C11H20FO3: 219.1396; found: 219.1389.
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Z-Selective Chromium(II)-Mediated Reductive Coupling Reaction of 1-Bromo-4-(tert-butyldiphenylsilyloxy)-1,1-difluorobutane (5) with Benzaldehyde; (Z)-8-(tert-Butyldiphenylsilyloxy)-5-fluoro-2-methyloct-5-en-4-ol (11h); Typical Procedure
To a suspension of anhydrous CrCl2 (1.11 g, 9.0 mmol) and LiI (0.10 g, 0.75 mmol) in DMF (6 mL) were added isovaleraldehyde (0.26 g, 3.0 mmol) and 1-bromo-4-(tert-butyldiphenylsilyloxy)-1,1-difluorobutane (5; 0.64 g, 1.5 mmol) at 0 °C. After stirring at r.t. for 4 h, the reaction was quenched with ice-cold H2O and the mixture was extracted with Et2O (3 ×). The combined organic layers were dried (Na2SO4); filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane–EtOAc, 5:1) to afford the pure product 11h; yield: 0.38 g (61%, 0.92 mmol); yellow oil.
IR (neat): 3388, 3071, 2957, 2931, 2859, 1709, 1471, 1428, 1388, 1362, 1111, 937, 823, 738, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.926 (3 H, d, J = 6.39 Hz), 0.932 (3 H, d, J = 6.39 Hz), 1.05 (9 H, s), 1.45–1.60 (3 H, m), 1.75 (1 H, m), 2.36 (2 H, q, J = 6.66 Hz), 3.69 (2 H, t, J = 6.66 Hz), 4.12 (1 H, dt, J = 15.79, 7.99 Hz), 4.88 (1 H, dt, J = 38.40, 6.66 Hz), 7.36–7.45 (6 H, m), 7.65–7.68 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 22.1, 23.0, 24.3, 26.8, 42.9, 63.1, 69.3 (d, J = 28.9 Hz), 103.1 (d, J = 14.1 Hz), 127.6, 129.6, 133.8, 135.6, 160.6 (d, J = 257.1 Hz).
19F NMR (376 MHz, CDCl3): δ = –125.73 (1 F, dd, J = 15.79, 38.40 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C25H35FO2SiNa: 437.2288; found: 437.2294.
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(Z)-5-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-phenylpent-2-en-1-ol (11a)
Yield: 0.30 g (67%, 0.68 mmol); yellow oil.
Physical and spectral data were in accordance with the literature values.[20]
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(Z)-5-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-(4-methoxyphenyl)pent-2-en-1-ol (11c)
Yield: 0.13 g (54%, 0.28 mmol); yellow oil.
IR (neat): 3405, 3070, 2930, 2857, 1611, 1512, 1471, 1427, 1249, 1174, 1111, 1035, 823, 740, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.03 (9 H, s), 2.06 (1 H, d, J = 4.80 Hz), 2.37 (2 H, q, J = 6.59 Hz), 3.68 (2 H, t, J = 6.59 Hz), 3.80 (3 H, s), 4.96 (1 H, dt, J = 37.95, 6.59 Hz), 5.15 (1 H, dd, J = 4.80, 11.34 Hz), 6.87–6.89 (2 H, m), 7.32–7.44 (8 H, m), 7.63–7.67 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 27.0 (d, J = 4.1 Hz), 55.2, 63.0 (d, J = 1.6 Hz), 72.3 (d, J = 32.1 Hz), 104.1 (d, J = 13.3 Hz), 113.9, 127.6, 128.0, 129.6, 131.7, 133.8, 135.5, 159.5, 159.7 (d, J = 256.2 Hz).
19F NMR (376 MHz, CDCl3): δ = –121.83 (1 F, dd, J = 11.34, 37.95 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C28H33FO3SiNa: 487.2081; found: 487.2075.
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(Z)-6-(tert-Butyldiphenylsilyloxy)-3-fluorohex-3-en-2-ol (11j)
Yield: 0.39 g (69%, 1.04 mmol); colorless oil.
IR (neat): 3362, 3071, 3050, 2957, 2931, 2858, 1709, 1472, 1428, 1389, 1362, 1111, 1005, 937, 823, 738, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.05 (9 H, s), 1.34 (3 H, d, J = 6.31 Hz), 1.55–1.65 (1 H, m), 2.35 (2 H, m), 3.69 (2 H, t, J = 6.79 Hz), 4.26 (1 H, dq, J = 13.74, 6.31 Hz), 4.88 (1 H, dt, J = 38.93, 6.79 Hz), 7.36–7.45 (6 H, m), 7.65–7.67 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 20.1 (d, J = 1.7 Hz), 26.8, 26.9 (d, J = 1.6 Hz), 63.0 (d, J = 1.6 Hz) 66.5 (d, J = 30.5 Hz), 102.0 (d, J = 14.0 Hz), 127.6, 129.6, 133.8, 135.6, 161.3 (d, J = 256.2 Hz).
19F NMR (376 MHz, CDCl3): δ = –124.45 (1 F, dd, J = 13.74, 38.93 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C22H29FO2SiNa: 395.1819; found: 395.1826.
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(Z)-7-(tert-Butyldiphenylsilyloxy)-4-fluoro-2-methylhept-4-en-3-ol (11g)
Yield: 0.40 g (67%, 1.00 mmol); yellow oil.
Physical and spectral data were in accordance with the literature values.[20]
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(Z)-8-(tert-Butyldiphenylsilyloxy)-5-fluoro-3-methyloct-5-en-4-ol (11k)
Yield: 0.41 g (49%, 0.99 mmol); diastereomeric ratio: 45:55; yellow oil.
IR (neat): 3404, 3071, 2961, 2931, 2858, 1707, 1463, 1428, 1384, 1362, 1262, 1111, 937, 822, 739, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.87–0.95 (6 H, m), 1.05 (9 H, s), 1.40–1.84 (4 H, m), 2.39 (2 H, q, J = 6.39 Hz), 3.72 (2 H, t, J = 6.39 Hz), 3.79 and 3.89 (1 H, dd and dd, J = 7.19, 19.48 Hz and J = 5.99, 15.69 Hz), 4.87 and 4.88 (1 H, dt and dt, J = 7.19, 38.64 Hz and J = 7.19, 38.50 Hz), 7.36–7.45 (6 H, m), 7.66–7.68 (4 H, m).
19F NMR (376 MHz, CDCl3): δ = –123.86 and –124.94 (1 F, dd and dd, J = 19.48, 38.64 Hz and 15.69, 38.50 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C25H35FO2SiNa: 437.2288; found: 437.2285.
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(Z)-6-(tert-Butyldiphenylsilyloxy)-3-fluoro-1-(4-methoxybenzyloxy)hex-3-en-2-ol (11l)
Yield: 0.20 g (38%, 0.39 mmol); colorless oil.
IR (neat): 3434, 3070, 2931, 2858, 1616, 1514, 1471, 1428, 1249, 1111, 1035, 822, 740, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.04 (9 H, s), 1.40–2.00 (1 H, m), 2.37 (2 H, q, J = 6.66 Hz), 3.50 (1 H, dd, J = 7.59, 9.59 Hz), 3.61 (1 H, dd, J = 4.00, 9.59 Hz), 3.67 (2 H, t, J = 6.66 Hz), 3.80 (3 H, s), 4.28 (1 H, ddd, J = 4.00, 7.59, 11.39 Hz), 4.48 (1 H, d, J = 11.99 Hz), 4.52 (1 H, d, J = 11.99 Hz), 4.99 (1 H, dt, J = 36.71, 6.66 Hz), 6.86–6.89 (2 H, m), 7.23–7.25 (2 H, m), 7.34–7.64 (6 H, m,), 7.65–7.66 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 26.9 (d, J = 1.7 Hz), 55.3, 63.0 (d, J = 1.7 Hz), 69.4 (d, J = 32.2 Hz), 71.0, 73.1, 104.1 (d, J = 12.4 Hz), 113.9, 127.6, 129.48, 129.58, 129.62, 133.8, 135.5, 157.7 (d, J = 255.4 Hz), 159.4.
19F NMR (376 MHz, CDCl3): δ = –123.36 (1 F, dd, J = 11.39, 36.71 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C30H37FO4SiNa: 531.2353; found: 531.2353.
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(Z)-2-Benzyloxy-7-(tert-butyldiphenylsilyloxy)-4-fluorohept-4-en-3-ol (11m)
This compound was inseparable from by-products; yield: 75% (19F NMR yield); diastereomeric ratio: 62:38.
#
Major Isomer (more polar)
1H NMR (400 MHz, CDCl3): δ = 1.05 (9 H, s), 1.19 (3 H, d, J = 6.39 Hz), 1.50–1.80 (1 H, m), 2.38 (2 H, q, J = 7.06 Hz), 3.68 (2 H, t, J = 7.06 Hz), 3.85–3.95 (1 H, m) 4.20–4.30 (1 H, m), 4.42–4.70 (2 H, m), 5.00 (1 H, dt, J = 38.43, 7.06 Hz), 7.26–7.44 (11 H, m), 7.65–7.67 (4 H, m).
19F NMR (376 MHz, CDCl3): δ = –123.04 (1 F, dd, J = 10.91, 38.43 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C30H37FO3SiNa: 515.2389; found: 515.2394.
#
Minor Isomer (less polar)
1H NMR (400 MHz, CDCl3): δ = 5.02 (1 H, dt, J = 37.37, 7.86 Hz).
19F NMR (376 MHz, CDCl3): δ = –123.94 (1 F, dd, J = 15.80, 37.37 Hz).
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Z-Selective Chromium(II)-Mediated Reductive Coupling Reaction of 1-Bromo-1,1-difluorononane (6) with Benzaldehyde; (Z)-2-Fluoro-1-phenyldec-2-en-1-ol (12a); Typical Procedure
To a suspension of anhydrous CrCl2 (0.22 g, 1.8 mmol) and LiI (0.020 g, 0.15 mmol) in DMF (1.2 mL) were added benzaldehyde (0.064 g, 0.6 mmol) and the substrate 6 (0.073 g, 0.3 mmol) at 0 °C. After stirring at r.t. for 4 h, the reaction was quenched with H2O and the mixture was extracted with Et2O (3 ×). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane–EtOAc, 3:1) to afford the pure product 12a; yield: 0.056 g (76%, 0.22 mmol); yellow oil.
IR (neat): 3364, 3032, 2926, 2856, 1708, 1495, 1455, 1379, 1273, 1192, 1111, 1024, 700 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, t, J = 6.79 Hz), 1.27–1.39 (10 H, m), 2.08–2.18 (3 H, m), 4.90 (1 H, dt, J = 37.87, 7.19 Hz), 5.21 (1 H, d, J = 13.17 Hz), 7.31–7.45 (5 H, m).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 23.3, 29.0, 29.1, 29.2, 31.8, 72.8 (d, J = 32.2 Hz), 107.8 (d, J = 13.3 Hz), 126.6, 128.2, 128.5, 139.7, 158.3 (d, J = 255.4 Hz).
19F NMR (376 MHz, CDCl3): δ = –124.22 (1 F, dd, J = 13.17, 37.87 Hz).
HRMS (FAB+): m/z [M]+ calcd for C16H23FO: 250.1733; found: 250.1729.
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(Z)-2-Fluoro-1-(4-methylphenyl)dec-2-en-1-ol (12b)
Yield: 76% (19F NMR yield). This compound could not be separated from the small amount of impurities.
IR (neat): 3368, 2925, 2856, 1708, 1514, 1459, 1273, 1111, 1044, 819, 768 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.90 (3 H, t, J = 5.60 Hz), 1.20–1.40 (10 H, m), 2.12 (2 H, q, J = 7.19 Hz), 2.26 (1 H, br s), 2.37 (3 H, s), 4.90 (1 H, dt, J = 37.03, 7.19 Hz), 5.16 (1 H, d, J = 12.41 Hz), 7.13–7.33 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 14.1, 21.1, 22.6, 23.3, 29.0, 29.1, 29.2, 31.8, 72.6 (d, J = 32.1 Hz), 107.6 (d, J = 14.1 Hz), 126.6, 129.2, 136.8, 138.0, 158.5 (d, J = 254.6 Hz).
19F NMR (376 MHz, CDCl3): δ = –124.11 (1 F, dd, J = 12.41, 37.03 Hz).
HRMS (FAB+): m/z [M]+ calcd for C17H25FO: 264.1889; found: 264.1884.
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(Z)-2-Fluoro-1-(4-methoxyphenyl)dec-2-en-1-ol (12c)
Yield: 0.065 g (80%, 0.23 mmol); yellow oil.
IR (neat): 3399, 2926, 2855, 1707, 1612, 1585, 1512, 1464, 1304, 1249, 1174, 1109, 1036, 832, 774 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, t, J = 6.79 Hz), 1.20–1.35 (11 H, m), 2.11 (2 H, q, J = 7.13 Hz), 3.81 (3 H, s), 4.89 (1 H, dt, J = 38.34, 7.13 Hz), 5.15 (1 H, dd, J = 3.60, 12.21 Hz), 6.90 (2 H, d, J = 8.59 Hz), 7.35 (2 H, d, J = 8.59 Hz).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 23.3, 28.99, 29.04, 29.2, 31.8, 55.2, 72.3 (d, J = 32.2 Hz), 107.4 (d, J = 13.3 Hz), 113.8, 127.9, 132.0, 158.6 (d, J = 254.6 Hz), 159.4.
19F NMR (376 MHz, CDCl3): δ = –123.86 (1 F, dd, J = 12.21, 38.34 Hz).
HRMS (FAB+): m/z [M]+ calcd for C17H25FO: 264.1889; found: 264.1894.
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(Z)-2-Fluoro-1-(4-fluorophenyl)dec-2-en-1-ol (12d)
Yield: 0.061 g (78%, 0.23 mmol); yellow oil.
IR (neat): 3358, 2926, 2856, 1707, 1605, 1509, 1465, 1227, 1157, 1097, 1015, 837, 783 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, t, J = 6.79 Hz), 1.20–1.40 (10 H, m), 2.10 (2 H, q, J = 7.19 Hz), 2.44 (1 H, br s), 4.89 (1 H, dt, J = 37.68, 7.19 Hz), 5.18 (1 H, d, J = 12.79 Hz), 7.03–7.09 (2 H, m), 7.38–7.41 (2 H, m).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 23.3, 28.99, 29.09, 29.14, 31.8, 72.1 (d, J = 32.2 Hz) 107.9 (d, J = 14.1 Hz), 115.3 (d, J = 21.5 Hz), 128.4 (d, J = 8.3 Hz), 135.5 (d, J = 2.5 Hz) 158.2 (d, J = 254.6 Hz), 162.6 (d, J = 246.4 Hz).
19F NMR (376 MHz, CDCl3): δ = –124.41 (1 F, dd, J = 12.79, 37.68 Hz).
HRMS (FAB+): m/z [M]+ calcd for C16H22F2O: 268.1639; found: 268.1632.
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(Z)-5-Fluoro-5-tridecen-4-ol (12f)
Yield: 0.051 g (81%, 0.24 mmol); yellow oil.
IR (neat): 3349, 2959, 2927, 2857, 1708, 1466, 1379, 1253, 1127, 1029, 845 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, t, J = 6.79 Hz), 0.94 (3 H, t, J = 7.19 Hz), 1.20–1.45 (12 H, m), 1.61–1.70 (3 H, m), 2.04–2.09 (2 H, m), 4.06 (1 H, dt, J = 17.25, 13.19 Hz), 4.79 (1 H, dt, J = 37.97, 7.19 Hz).
13C NMR (100 MHz, CDCl3): δ = 13.8, 14.1, 18.7, 22.6, 23.2, 29.0, 29.1, 29.3, 31.8, 36.0, 70.8 (d, J = 29.8 Hz), 106.7 (d, J = 14.1 Hz), 159.2 (d, J = 255.4 Hz).
19F NMR (376 MHz, CDCl3): δ = –127.84 (1 F, dd, J = 17.25, 37.97 Hz).
HRMS (EI+): m/z [M]+ calcd for C13H25FO: 216.1889; found: 216.1891.
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(Z)-4-Fluoro-2-methyldodec-4-en-3-ol (12g)
Yield: 0.044 g (70%, 0.20 mmol); yellow oil.
IR (neat): 3387, 2958, 2926, 2857, 1707, 1467, 1381, 1281, 1168, 1103, 1021, 934, 831 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, t, J = 6.79 Hz), 0.91 (3 H, d, J = 6.79 Hz), 0.98 (3 H, d, J = 6.79 Hz), 1.20–1.40 (10 H, m), 1.70–1.75 (1 H, m), 1.85–1.95 (1 H, m), 2.09 (2 H, q, J = 7.59 Hz), 3.72 (1 H, dt, J = 19.37, 6.79 Hz), 4.77 (1 H, dt, J = 37.41, 7.59 Hz).
13C NMR (100 MHz, CDCl3): δ = 14.1, 17.9, 18.9, 22.6, 23.2, 29.0, 29.1, 29.3, 31.3, 31.8, 76.5 (d, J = 32.2 Hz), 107.6 (d, J = 14.1 Hz), 158.5 (d, J = 256.2 Hz).
19F NMR (376 MHz, CDCl3): δ = –126.97 (1 F, dd, J = 19.37, 37.41 Hz).
HRMS (EI+): m/z [M]+ calcd for C13H25FO: 216.1889; found: 216.1897.
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(Z)-4-Fluoro-2,2-dimethyldodec-4-en-3-ol (12h)
Yield: 82% (19F NMR yield). This compound could not be separated from the small amount of impurities.
IR (neat): 3421, 2956, 2926, 2857, 1703, 1466, 1365, 1288, 1114, 1065, 1013, 910, 848, 768 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, t, J = 6.39 Hz), 0.96 (9 H, s), 1.20–1.35 (11 H, m), 2.09 (2 H, q, J = 7.19 Hz), 3.71 (1 H, d, J = 20.64 Hz), 4.75 (1 H, dt, J = 37.88, 7.19 Hz).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.6, 23.2, 26.0, 29.1, 29.31, 29.32, 31.8, 34.8, 78.8 (d, J = 27.3 Hz), 108.5 (d, J = 14.1 Hz), 158.4 (d, J = 257.9 Hz).
19F NMR (376 MHz, CDCl3): δ = –120.38 (1 F, dd, J = 20.64, 37.88 Hz).
HRMS (FAB+): m/z [M]+ calcd for C14H27FO: 230.2046; found: 230.2043.
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Azide Compounds; (Z)-2-Azido-6-(tert-butyldiphenylsilyloxy)-3-fluoro-1-(4-methoxybenzyloxy)hex-3-ene (14l), Typical Procedure
To a mixture of β-fluoroallylic alcohol derivative 11l (0.26 g 0.51 mmol), NaN3 (0.96 g, 15 mmol), and DMAP (0.25 g, 2.02 mmol) in CH2Cl2 (5.1 mL) were added MsCl (0.14 g, 1.26 mmol) at 0 °C. The mixture was stirred at r.t. for 30 min. Then, DMSO (3.37 mL) was added to the reaction mixture and the whole was stirred for additional 3 h. The reaction was quenched with H2O and the mixture was extracted with Et2O (3 ×). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane–EtOAc, 3:1) to afford the pure product 14l; yield: 0.23 g (85%, 0.43 mmol); pale yellow oil.
In the case of 11a and 11c, the reaction proceeded in a highly regioselective manner to afford the corresponding azide compounds, 15a and 15c in a pure form. For other substrates, the reaction took place in a low regioselective manner to give the corresponding adducts as an inseparable regioisomeric mixture. Therefore, the mixture was employed for the next reaction without further purification.
IR (neat): 2931, 2857, 2103, 1613, 1514, 1471, 1428, 1362, 1303, 1250, 1173, 1111, 1037, 822, 739, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.04 (9 H, s), 2.38 (2 H, q, J = 6.29 Hz), 3.55 (1 H, dd, J = 7.98, 9.59 Hz), 3.64–3.70 (1 H, m), 3.68 (2 H, t, J = 6.29 Hz), 3.80 (3 H, s), 4.08 (1 H, ddd, J = 4.79, 7.98, 17.15 Hz), 4.48 (1 H, d, J = 11.49 Hz), 4.52 (1 H, d, J = 11.49 Hz) 5.00 (1 H, dt, J = 36.92, 6.29 Hz), 6.87–6.88 (2 H, m), 7.24–7.45 (8 H, m), 7.65–7.66 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 27.1 (d, J = 4.1 Hz), 55.2, 61.6 (d, J = 29.0 Hz), 62.8 (d, J = 1.6 Hz), 69.2, 73.2, 106.9 (d, J = 12.5 Hz), 113.9, 127.6, 129.4, 129.5, 129.6, 133.7, 135.5, 154.4 (d, J = 256.2 Hz), 159.4.
19F NMR (376 MHz, CDCl3): δ = –120.86 (1 F, dd, J = 17.15, 36.92 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C30H36FN3O3SiNa: 556.2408; found: 556.2401.
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(Z)-3-Azido-5-(tert-butyldiphenylsilyloxy)-2-fluoro-1-phenylpent-1-ene (15a)
Yield: 0.19 g (60%, 0.41 mmol); yellow oil.
IR (neat): 3070, 2958, 2931, 2857, 2101, 1471, 1428, 1251, 1112, 822, 739, 700 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.07 (9 H, s), 1.90–2.08 (1 H, m), 2.00–2.03 (1 H, m), 3.80 (2 H, m), 4.34 (1 H, dt, J = 22.39, 7.29 Hz), 5.77 (1 H, d, J = 38.65 Hz), 7.29–7.44 (9 H, m), 7.50–7.52 (2 H, m), 7.63–7.68 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 33.9, 59.7, 60.2 (d, J = 7.2 Hz), 109.2 (d, J = 6.5 Hz), 127.7 (d, J = 4.1 Hz), 127.9 (d, J = 2.5 Hz), 128.6, 128.9 (d, J = 7.4 Hz), 129.8 (d, J = 4.1 Hz), 132.2 (d, J = 2.5 Hz), 133.3 (d, J = 4.9 Hz), 135.5 (d, J = 2.4 Hz), 156.2 (d, J = 268.7 Hz).
19F NMR (376 MHz, CDCl3): δ = –116.84 (1 F, dd, J = 22.39, 38.65 Hz).
HRMS (FAB+): m/z [M]+ calcd for C27H30FN3OSi: 459.2142; found: 459.2148.
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(Z)-3-Azido-5-(tert-butyldiphenylsilyloxy)-2-fluoro-1-(4-methoxyphenyl)pent-1-ene (15c)
Yield: 0.12 g (45%, 0.24 mmol); yellow oil.
IR (neat): 3071, 2957, 2931, 2857, 2101, 1608, 1513, 1463, 1428, 1299, 1254, 1180, 1112, 1034, 860, 823, 739, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.06 (9 H, s), 1.90–1.98 (1 H, m), 1.99–2.07 (1 H, m), 3.72–3.89 (2 H, m), 3.83 (3 H, s), 4.32 (1 H, dt, J = 21.99, 7.39 Hz), 5.70 (1 H, d, J = 38.65 Hz), 6.88–6.90 (2 H, m), 7.31–7.47 (8 H, m), 7.62–7.70 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 33.9, 55.3, 59.8, 60.4 (d, J = 27.3 Hz), 108.8 (d, J = 7.4 Hz), 114.0, 124.8 (d, J = 3.3 Hz), 127.7 (d, J = 4.2 Hz), 129.8 (d, J = 4.2 Hz), 130.3 (d, J = 7.4 Hz), 133.3 (d, J = 5.7 Hz), 135.5 (d, J = 2.5 Hz), 154.8 (d, J = 226.8 Hz), 159.1 (d, J = 2.5 Hz).
19F NMR (376 MHz, CDCl3): δ = –119.91 (1 F, dd, J = 21.99, 38.65 Hz).
HRMS (FAB+): m/z [M]+ calcd for C28H32FN3O2Si: 489.2248; found: 489.2245.
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β-Fluoroallylic Amines 16 and 17; (Z)-5-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-phenylpent-1-en-3-amine (17a); Typical Procedure
To a solution of the azide compound 15a (0.19 g 0.41 mmol) in THF (1.37 mL)–H2O (0.075 mL) was added PPh3 (0.22 g, 0.82 mmol) at r.t. The mixture was stirred at 50 °C for 24 h. The reaction mixture was purified by silica gel column chromatography (hexane–EtOAc, 2:1) to afford the pure product 17a; yield: 0.15 g (85%, 0.35 mmol); yellow oil.
IR (neat): 3070, 2930, 2857, 1687, 1589, 1492, 1471, 1448, 1427, 1389, 1111, 1049, 998, 937, 915, 823, 739, 702, 613 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.06 ( H, s), 1.70 (2 H, br s), 1.82–1.89 (1 H, m), 1.93–1.98 (1 H, m), 3.74–3.86 (3 H, m), 5.70 (1 H, d, J = 40.20 Hz), 7.22–7.49 (11 H, m), 7.64–7.68 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 36.9, 51.3 (d, J = 28.1 Hz), 61.1, 105.4 (d, J = 7.4 Hz), 127.0 (d, J = 7.4 Hz), 127.7 (d, J = 2.4 Hz), 128.4, 128.6 (d, J = 6.6 Hz), 129.6 (d, J = 2.4 Hz), 133.3 (d, J = 4.1 Hz), 133.5 (d, J = 4.1 Hz), 135.5, 162.2 (d, J = 267.8 Hz).
19F NMR (376 MHz, CDCl3): δ = –117.59 (1 F, dd, J = 18.24, 40.20 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C27H33FNOSi: 434.2315; found: 434.2324.
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(Z)-7-(tert-Butyldiphenylsilyloxy)-4-fluoro-2-methylhept-4-en-3-amine (16g)
Yield: 0.095 g (35%); 0.24 mmol; colorless oil.
IR (neat): 3071, 2958, 2930, 2857, 1703, 1589, 1471, 1428, 1386, 1362, 1260, 1111, 936, 822, 738, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.92 (3 H, d, J = 6.79 Hz), 0.95 (3 H, d, J = 6.79 Hz), 1.05 (9 H, s), 1.41 (2 H, br s), 1.80 (1 H, m), 2.36 (2 H, q, J = 6.93 Hz), 2.99 (1 H, dd, J = 6.79, 20.23 Hz), 3.68 (2 H, t, J = 6.93 Hz), 4.74 (1 H, dt, J = 38.01, 6.93 Hz), 7.36–7.45 (6 H, m), 7.66–7.68 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 18.4, 19.1, 19.6, 26.8, 27.0 (d, J = 16.6 Hz), 31.1, 59.1 (d, J = 27.3 Hz), 63.3 (d, J = 1.7 Hz), 102.2 (d, J = 14.9 Hz), 127.6, 129.5, 133.8, 135.5, 161.8 (d, J = 257.0 Hz).
19F NMR (376 MHz, CDCl3): δ = –122.52 (1 F, dd, J = 20.23, 38.01 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C24H35FNOSi: 400.2472; found: 400.2481.
#
(Z)-8-(tert-Butyldiphenylsilyloxy)-5-fluoro-2-methyloct-5-en-4-amine (16h)
Yield: 0.077 g (28%, 0.19 mmol); yellow oil.
IR (neat): 3071, 2956, 2930, 2857, 1703, 1471, 1428, 1386, 1362, 1111, 1022, 937, 822, 738, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.90 (6 H, d, J = 6.39 Hz), 1.05 (9 H, s), 1.26–1.36 (1 H, m), 1.42–1.56 (3 H, m), 1.62–1.72 (1 H, m), 2.34 (2 H, q, J = 6.69 Hz), 3.32 (1 H, dt, J = 20.63, 7.39 Hz), 3.67 (2 H, t, J = 6.69 Hz), 4.74 (1 H, dt, J = 38.04, 6.69 Hz), 7.36–7.45 (6 H, m), 7.66–7.68 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 22.4, 22.6, 24.9, 26.8, 27.0 (d, J = 4.1 Hz), 43.1, 51.2 (d, J = 28.0 Hz), 63.2 (d, J = 1.6 Hz), 101.3 (d, J = 14.9 Hz), 127.6 (d, J = 5.8 Hz), 129.5, 133.8 (d, J = 1.6 Hz), 135.5, 162.6 (d, J = 257.1 Hz).
19F NMR (376 MHz, CDCl3): δ = –125.31 (1 F, dd, J = 20.63, 38.04 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C25H37FNOSi: 414.2628; found: 414.2630.
#
(Z)-6-(tert-Butyldiphenylsilyloxy)-3-fluorohex-3-en-2-amine (16j)
Yield: 0.16 g (49%, 0.43 mmol); colorless oil.
IR (neat): 3072, 3049, 2959, 2931, 2858, 1704, 1472, 1428, 1389, 1112, 1027, 937, 823, 791, 737, 703, 613 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.06 (9 H, s), 1.23 (3 H, d, J = 6.79 Hz), 1.41 (2 H, br s), 2.31–2.38 (2 H, m), 3.46 (1 H, dq, J = 14.67, 6.79 Hz), 3.68 (2 H, t, J = 6.59 Hz), 4.75 (1 H, dt, J = 37.35, 7.49 Hz), 7.36–7.45 (6 H, m), 7.67–7.69 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 20.4 (d, J = 1.7 Hz), 26.8, 26.9 (d, J = 4.9 Hz), 48.0 (d, J = 29.8 Hz), 63.2 (d, J = 1.6 Hz), 99.9 (d, J = 15.8 Hz), 127.6, 129.5, 133.8, 135.5, 163.7 (d, J = 256.2 Hz).
19F NMR (376 MHz, CDCl3): δ = –121.96 (1 F, dd, J = 14.67, 37.35 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C22H31FNOSi: 372.2159; found: 372.2158.
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(Z)-8-(tert-Butyldiphenylsilyloxy)-5-fluoro-3-methyloct-5-en-4-amine (16k)
Yield: 0.082 g (52%, 0.20 mmol); yellow oil; diastereomeric ratio: 48:52.
IR (neat): 3071, 2960, 2931, 2858, 1472, 1428, 1111, 1021, 823, 738, 701, 613 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.898 (3 H, t, J = 7.19 Hz), 0.900 (3 H, d, J = 6.79 Hz), 1.05 (9 H, s), 1.16 (1 H, m), 1.44 (2 H, br s), 1.46–1.63 (2 H, m), 2.35 (2 H, q, J = 7.29 Hz), 3.08 and 3.15 (1 H, dd and dd, J = 6.79, 20.73 Hz and 5.60, 18.19 Hz), 3.68 (2 H, t, J = 7.29 Hz), 4.73 and 4.75 (1 H, dt and dt, J = 38.17, 7.29 Hz), 7.30–7.50 (6 H, m), 7.60–7.70 (4 H, m).
19F NMR (376 MHz, CDCl3): δ = –121.26 (1 F, dd, J = 18.19, 38.17 Hz), –122.36 (1 F, dd, J = 20.73, 38.17 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C25H37FNOSi: 414.2628; found: 414.2627.
#
(Z)-6-(tert-Butyldiphenylsilyloxy)-3-fluoro-1-(4-methoxybenzyloxy)hex-3-en-2-amine (16l)
Yield: 0.17 g (85%, 0.34 mmol); colorless oil.
IR (neat): 3070, 2931, 2857, 1612, 1587, 1514, 1471, 1428, 1362, 1302, 1249, 1173, 1111, 1037, 822, 739, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.05 (9 H, s), 1.55–1.65 (2 H, br s), 2.35 (2 H, q, J = 6.79 Hz), 3.36–3.42 (1 H, m), 3.55–3.64 (1 H , m), 3.66 (2 H, t, J = 6.79 Hz), 3.80 (3 H, s), 4.47 (2 H, s), 4.86 (1 H, dt, J = 38.11, 6.79 Hz), 6.37 (2 H, d, J = 8.59 Hz), 7.23 (2 H, d, J = 8.59 Hz), 7.27–7.44 (6 H, m), 7.65–7.67 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 26.8, 26.9 (d, J = 4.2 Hz), 52.6 (d, J = 28.9 Hz), 55.1, 63.1 (d, J = 1.7 Hz), 71.9, 72.9, 102.5 (d, J = 14.1 Hz), 113.7, 127.6, 129.3, 129.5, 129.9, 133.5, 133.8, 159.2, 160.0 (d, J = 255.4 Hz).
19F NMR (376 MHz, CDCl3): δ = –120.58 (1 F, dd, J = 13.53, 38.11 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C30H38FNO3SiNa: 530.2503; found: 530.2493.
#
(Z)-2-Benzyloxy-7-(tert-butyldiphenylsilyloxy)-4-fluorohept-4-en-3-amine (16m)
Yield: 0.028 g (40%, 0.057 mmol); colorless oil; diastereomeric ratio: 27:73.
19F NMR (376 MHz, CDCl3): δ = –119.75 and –121.13 (dd and dd, J = 14.67, 39.11 Hz).
#
(Z)-5-(tert-Butyldiphenylsilyloxy)-2-fluoro-1-(4-methoxyphenyl)pent-1-en-3-amine (17c)
Yield: 0.69 g (84%, 0.20 mmol); colorless oil.
IR (neat): 3070, 2999, 2931, 2857, 1608, 1512, 1464, 1428, 1389, 1297, 1251, 1179, 1111, 1036, 937, 855, 823, 739, 703, 613 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.06 (9 H, s), 1.69 (2 H, br s), 1.84 (1 H, m), 1.95 (1 H, m), 3.80 (3 H, m), 3.82 (3 H, s), 5.63 (1 H, d, J = 40.87 Hz), 6.87 (2 H, m), 7.31–7.44 (8 H, m), 7.65–7.69 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 36.9, 51.2 (d, J = 28.1 Hz), 55.2, 61.1, 104.9 (d, J = 7.4 Hz), 113.8, 125.9 (d, J = 2.5 Hz), 127.7 (d, J = 2.4 Hz), 129.6 (d, J = 2.5 Hz), 129.8 (d, J = 6.6 Hz), 133.5 (d, J = 2.4 Hz), 135.5, 158.5 (d, J = 2.5 Hz), 160.8 (d, J = 264.5 Hz).
19F NMR (376 MHz, CDCl3): δ = –120.64 (1 F, dd, J = 19.55, 40.87 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C28H35FNO2Si: 464.2421; found: 464.2420.
#
(Z)-1-(tert-Butyldiphenylsilyloxy)-4-fluoro-6-methylhept-4-en-3-amine (17g)
Yield: 0.045 g (17%, 0.11 mmol); colorless oil.
IR (neat): 3385, 3071, 2958, 2931, 2858, 1702, 1589, 1471, 1428, 1389, 1278, 1112, 1047, 936, 823, 738, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.95 (3 H, d, J = 6.92 Hz), 0.98 (3 H, d, J = 6.92 Hz), 1.04 (9 H, s), 1.46 (2 H, br s), 1.68–1.76 (1 H, m), 1.80–1.88 (1 H, m), 2.72 (1 H, dsept, J = 9.65, 6.92 Hz), 3.56 (1 H, dt, J = 18.51, 6.79 Hz), 3.74 (2 H, m), 4.55 (1 H, dd, J = 9.65, 38.18 Hz), 7.36–7.44 (6 H, m), 7.65–7.68 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.2, 23.0, 23.1 (d, J = 1.7 Hz), 23.6 (d, J = 4.5 Hz), 26.8, 36.9, 50.3 (d, J = 28.9 Hz), 61.1, 112.5 (d, J = 14.9 Hz), 127.7 (d, J = 1.7 Hz), 129.6, 133.7 (d, J = 4.5 Hz), 135.5, 159.5 (d, J = 254.5 Hz).
19F NMR (376 MHz, CDCl3): δ = –126.64 (1 F, dd, J = 18.51, 38.18 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C24H35FNOSi: 400.2472; found: 400.2481.
#
(Z)-1-(tert-Butyldiphenylsilyloxy)-4-fluoro-7-methyloct-4-en-3-amine (17h)
Yield: 0.150 g (54%, 0.36 mmol); yellow oil.
IR (neat): 3385, 3071, 2956, 2930, 2858, 1702, 1471, 1428, 1388, 1111, 1048, 823, 737, 702, 613 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.88 (3 H, d, J = 6.79 Hz), 0.89 (3 H, d, J = 6.39 Hz), 1.05 (9 H, s), 1.56 (2 H, br s), 1.57–1.60 (1 H, m), 1.70–1.78 (1 H, m), 1.81–1.91 (1 H, m), 1.92–1.97 (2 H, m), 3.61 (1 H, dt, J = 19.17, 6.79 Hz), 3.70–3.81 (2 H, m), 4.69 (1 H, dt, J = 38.54, 7.79 Hz), 7.36–7.48 (6 H, m), 7.65–7.68 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 19.1, 22.17, 22.19, 26.8, 28.3 (d, J = 1.6 Hz), 32.3 (d, J = 4.1 Hz), 36.9, 50.4 (d, J = 29.0 Hz), 61.1, 103.7 (d, J = 14.9 Hz), 127.6 (d, J = 2.4 Hz), 129.6, 133.6 (d, J = 5.0 Hz), 135.5, 161.5 (d, J = 255.4 Hz).
19F NMR (376 MHz, CDCl3): δ = –125.85 (1 F, dd, J = 19.17, 38.54 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C25H37FNOSi: 414.2628; found: 414.2625.
#
(Z)-1-(tert-Butyldiphenylsilyloxy)-4-fluorohex-4-en-3-amine (17j)
Yield: 0.11 g (33%, 0.29 mmol); colorless oil.
IR (neat): 3384, 3071, 3050, 2930, 2858, 1709, 1589, 1482, 1428, 1390, 1112, 1048, 984, 823, 739, 702, 688 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.05 (9 H, s), 1.55–1.59 (5 H, m), 1.71–1.76 (1 H, m), 1.80–1.88 (1 H, m), 3.62 (1 H, dt, J = 19.37, 6.79 Hz), 3.75 (2 H, m), 4.71 (1 H, dq, J = 37.42, 6.79 Hz), 7.36–7.45 (6 H, m), 7.65–7.68 (4 H, m).
13C NMR (100 MHz, CDCl3): δ = 8.5 (d, J = 6.6 Hz), 19.1, 26.8, 36.8, 50.3 (d, J = 28.1 Hz), 61.0, 99.3 (d, J = 15.8 Hz), 127.6, 129.6, 133.6, 135.5, 161.7 (d, J = 255.4 Hz).
19F NMR (376 MHz, CDCl3): δ = –126.69 (1 F, dd, J = 19.37, 37.42 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C22H31FNOSi: 372.2159; found: 372.2149.
#
(Z)-1-(tert-Butyldiphenylsilyloxy)-4-fluoro-6-methyloct-4-en-3-amine (17k)
Yield: 0.050 g (31%, 0.12 mmol); colorless oil; diastereomeric ratio: 49:51.
IR (neat): 3071, 2959, 2930, 2857, 1472, 1461, 1428, 1112, 1048, 823, 738, 702, 613 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.81 and 0.85 (3 H, t and t, J = 7.19 Hz), 0.94 and 1.00 (3 H, d and d, J = 6.79 Hz), 1.05 (9 H, s), 1.16–1.23 (1 H, m), 1.24–1.40 (1 H, m), 1.50–1.70 (2 H, br s), 1.68–1.80 (1 H, m), 1.80–1.90 (1 H, m), 2.47 (1 H, m), 3.59 (1 H, m), 3.75 (2 H, m), 4.41 and 4.49 (1 H, dd and dd, J = 8.34, 38.36 Hz and 7.79, 38.86 Hz), 7.35–7.44 (6 H, m), 7.65–7.68 (4 H, m).
19F NMR (376 MHz, CDCl3): δ = –126.21 (1 F, dd, J = 17.11, 38.36 Hz), –126.95 (1 F, dd, J = 19.55, 39.86 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C25H37FNOSi: 414.2628; found: 414.2627.
#
(Z)-6-Benzyloxy-1-(tert-butyldiphenylsilyloxy)-4-fluorohept-4-en-3-amine (17m)
Yield: 0.034 g (48%, 0069 mmol); yellow oil; diastereomeric ratio: 27:73.
19F NMR (376 MHz, CDCl3): δ = –120.55 and –121.15 (dd and dd, J = 17.93, 36.66 Hz).
#
tert-Butyl (Z)-3-Fluoro-6-hydroxyhex-3-en-2-ylcarbamate (18j); Typical Procedure
To a solution of (Z)-6-(tert-butyldiphenylsilyloxy)-3-fluorohex-3-en-2-amine (16j; 0.19 g, 0.5 mmol) and Et3N (0.05 mL, 0.6 mmol) in CH2Cl2 (1.7 mL) was added (Boc)2O (0.13 g, 0.6 mmol) at 0 °C. The mixture was stirred at r.t. for 1 h. Then, the reaction was quenched with H2O and the mixture was extracted with CH2Cl2 (3 ×). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting residue was used in the next step without further purification. To a THF solution of the above alcohol was added TBAF (0.55 mL, 0.55 mmol) at r.t. After stirring the mixture at that temperature for 2 h, addition of H2O followed by extractive workup and purification by column chromatography (hexane–EtOAc, 2:1) afforded the desired alcohol 18j; yield: 0.086 g (74%, 0.37 mmol); colorless oil.
IR (neat): 3328, 2979, 2933, 1692, 1527, 1454, 1428, 1391, 1367, 1251, 1171, 1112, 1056, 862, 735, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.26 (3 H, d, J = 6.96 Hz), 1.40 (9 H, s), 1.65 (1 H, br s), 2.23–2.36 (2 H, m), 3.61 (2 H, t, J = 6.32 Hz), 4.22–4.26 (1 H, m), 4.63 (1 H, br s), 4.78 (1 H, dt, J = 37.20, 7.52 Hz).
13C NMR (100 MHz, CDCl3): δ = 18.5, 27.0 (d, J = 3.9 Hz), 28.3, 47.4 (d, J = 27.7 Hz), 61.7, 79.7, 101.6 (d, J = 14.4 Hz), 154.9, 160.3 (d, J = 257.6 Hz).
19F NMR (376 MHz, CDCl3): δ = –123.24 (1 F, dd, J = 16.18, 37.20 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C11H20FNO3Na: 256.1325; found: 256.1319.
#
tert-Butyl (Z)-4-Fluoro-7-hydroxy-2-methylhept-4-en-3-ylcarbamate (18g)
Yield: 0.39 g (65%, 1.48 mmol); yellow oil.
IR (neat): 3334, 2966, 2933, 2875, 1696, 1504, 1469, 1391, 1367, 1251, 1171, 1044, 1011, 876, 737, 479, 418 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.926 (3 H, d, J = 6.76 Hz), 0.933 (3 H, d, J = 6.76 Hz), 1.43 (9 H, s), 1.86 (1 H, octet, J = 6.90 Hz), 1.99 (1 H, br s), 2.31–2.40 (2 H, m), 3.62 (2 H, t, J = 6.36 Hz), 3.86 (1 H, dt, J = 21.91, 8.48 Hz), 4.77 (1 H, dt, J = 37.60, 7.58 Hz).
13C NMR (100 MHz, CDCl3): δ = 18.6, 19.5, 27.2 (d, J = 4.1 Hz), 28.4, 30.1, 58.0 (d, J = 27.6 Hz), 61.9, 79.8, 103.6 (d, J = 14.2 Hz), 155.5, 158.6 (d, J = 258.0 Hz).
19F NMR (376 MHz, CDCl3): δ = –122.98 (1 F, dd, J = 21.91, 37.60 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C13H25FNO3: 262.1818; found: 262.1820.
#
tert-Butyl (Z)-5-Fluoro-8-hydroxy-2-methyloct-5-en-4-ylcarbamate (18h)
Yield: 0.22 g (86%, 0.80 mmol); yellow oil.
IR (neat): 3330, 2959, 2871, 1692, 1527, 1470, 1391, 1367, 1283, 1252, 1171, 1117, 1046, 872 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.916 (3 H, d, J = 6.60 Hz), 0.919 (3 H, d, J = 6.52 Hz), 1.43 (9 H, s), 1.35–1.55 (2 H, m), 1.56–1.70 (1 H, m), 1.80–1.95 (1 H, br s), 2.25–2.44 (2 H, m), 3.63 (2 H, t, J = 6.34 Hz), 4.08–4.24 (1 H, m), 4.63–4.67 (1 H, m), 4.80 (1 H, dt, J = 37.41, 7.56 Hz).
13C NMR (100 MHz, CDCl3): δ = 22.6, 22.7, 25.0, 27.5 (d, J = 3.7 Hz), 28.6, 41.5, 50.8 (d, J = 28.2 Hz), 62.0, 80.0, 103.1 (d, J = 14.1 Hz), 155.5, 159.6 (d, J = 258.2 Hz).
19F NMR (376 MHz, CDCl3): δ = –125.09 (1 F, dd, J = 21.76, 37.41 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C14H26FNO3Na: 298.1794; found: 298.1804.
#
tert-Butyl (Z)-3-Fluoro-6-hydroxy-1-(4-methoxybenzyloxy)hex-3-en-2-ylcarbamate (18l)
Due to unidentified inseparable by-products, this compound could not be isolated in pure form; yield: 96% (19F NMR yield).
1H NMR (400 MHz, CDCl3): δ = 1.44 (9 H, s), 1.85–2.05 (1 H, m), 2.29–2.43 (2 H, m), 3.53 (1 H, dd, J = 4.98, 9.66 Hz), 3.62 (2 H, t, J = 6.32 Hz), 3.60–3.65 (1 H, m), 3.81 (3 H, s), 4.37 (1 H, br s), 4.47 (2 H, s), 4.86 (1 H, dt, J = 37.32, 7.60 Hz), 4.96–5.11 (1 H, m), 6.88 (2 H, d, J = 8.64 Hz), 7.23 (2 H, d, J = 8.64 Hz).
19F NMR (376 MHz, CDCl3): δ = –120.70 (1 F, dd, J = 11.14, 37.32 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C19H28FNO5Na: 392.1849; found: 392.1850.
The corresponding carboxylic acid was converted into the methyl ester through treatment of the acid with an excess amount of diazomethane.
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Methyl (Z)-5-(tert-Butoxycarbonylamino)-4-fluoro-7-methyloct-3-enoate (19h); Typical Procedure
To a solution of tert-butyl (Z)-5-fluoro-8-hydroxy-2-methyloct-5-en-4-yl carbamate (18h; 0.21 g, 0.76 mmol) in acetone (9.45 mL) was added Jones reagent [readily prepared by mixing of CrO3 (0.39 g, 3.91 mmol), H2O (1.15 mL), and H2SO4 (0.38 mL) at 0 °C] at 0 °C. The mixture was stirred at that temperature for 3.5 h. The reaction was quenched with i-PrOH–H2O (1:1 v/v) and the mixture was extracted with EtOAc (3 ×), and washed with brine. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to give the corresponding carboxylic acid. Thus obtained carboxylic acid was dissolved in Et2O (10 mL), and the mixture was cooled to 0 °C. To this reaction mixture was added dropwise an excess amount of an ethereal solution of diazomethane [readily prepared via heating the mixture of KOH (0.56 g, 9.89 mmol), N-methyl-N-nitroso-p-toluenesufonamide (1.81 g, 8.45 mmol) in Et2O (ca. 20 mL)/H2O (ca. 1 mL)] at 0 °C. After about 1 h, the reaction was quenched with AcOH, and the mixture was concentrated in vacuo. The residue was neutralized with sat. aq NaHCO3 and extracted with EtOAc (3 ×). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (hexane–EtOAc, 3:1) to give 19h; yield: 0.16 g (69%, 0.52 mmol) over 2 steps; yellow oil.
IR (neat): 3360, 2958, 2871, 1712, 1518, 1439, 1367, 1252, 1170, 1044, 1023, 951, 907, 780 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.92 (6 H, d, J = 6.60 Hz), 1.43 (9 H, s), 1.35–1.55 (2 H, m), 1.58–1.70 (1 H, m), 3.10–3.15 (2 H, m), 3.68 (3 H, s), 4.15–4.35 (1 H, m), 4.62 (1 H, d, J = 8.44 Hz), 5.01 (1 H, dt, J = 36.29, 7.00 Hz).
13C NMR (100 MHz, CDCl3): δ = 22.5, 22.8, 25.0, 28.6, 29.3 (d, J = 5.7 Hz), 41.6, 50.3 (d, J = 28.1 Hz), 52.2, 79.9, 98.6 (d, J = 13.1 Hz), 155.2, 160.2 (d, J = 260.7 Hz), 171.7 (d, J = 1.7 Hz).
19F NMR (376 MHz, CDCl3): δ = –121.50 (1 F, dd, J = 19.54, 36.29 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C12H26FNO4Na: 326.1744; found: 326.1751.
#
Methyl (Z)-5-(tert-Butoxycarbonylamino)-4-fluoro-6-methylhept-3-enoate (19g)
Yield: 0.29 g (68%, 0.99 mmol); yellow oil.
IR (neat): 3362, 2970, 1744, 1709, 1513, 1469, 1438, 1391, 1367, 1255, 1171, 1041, 1011, 949, 879, 808, 487 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.93 (3 H, d, J = 6.74 Hz), 0.94 (3 H, d, J = 6.74 Hz), 1.43 (9 H, s), 1.89 (1 H, octet, J = 6.74 Hz), 3.14 (2 H, m), 3.68 (3 H, s), 3.97 (1 H, dt, J = 19.98, 8.57 Hz), 4.72 (1 H, d, J = 9.16 Hz), 4.97 (1 H, dt, J = 36.49, 7.16 Hz).
13C NMR (100 MHz, CDCl3): δ = 18.2, 19.3, 28.3, 29.0 (d, J = 5.9 Hz), 30.1, 51.8, 57.2 (d, J = 27.2 Hz), 79.5, 99.1 (d, J = 13.0 Hz), 155.2, 159.2 (d, J = 261.0 Hz), 171.4 (d, J = 1.8 Hz).
19F NMR (376 MHz, CDCl3): δ = –119.72 (1 F, dd, J = 19.98, 36.49 Hz).
HRMS (FAB+): m/z [M + H]+ calcd for C14H25FNO4: 290.1768; found: 290.1769.
#
(Z)-5-(tert-Butoxycarbonylamino)-4-fluorohex-3-enoic Acid (19j)
The methyl esterification with diazomethane was not carried out because the corresponding carboxylic acid could be isolated in a pure form; yield: 47 mg (45%, 0.19 mmol); colorless oil.
IR (neat): 3327, 2980, 2934, 1715, 1524, 1455, 1394, 1368, 1252, 1169, 1105, 1059, 951, 914, 864, 735 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.31 (3 H, d, J = 6.96 Hz), 1.44 (9 H, s), 3.18 (2 H, d, J = 7.04 Hz), 4.33–4.35 (1 H, m), 4.68 (1 H, m), 5.02 (1 H, dt, J = 35.96, 7.04 Hz), 9.20–9.40 (1 H, m).
13C NMR (100 MHz, CDCl3): δ = 18.5, 28.3, 28.9 (d, J = 3.9 Hz), 47.0 (d, J = 23.6 Hz), 80.0, 97.1 (d, J = 16.5 Hz), 154.8, 160.8 (d, J = 261.2 Hz), 176.1.
19F NMR (376 MHz, CDCl3): δ = –119.48 (1 F, dd, J = 14.34, 35.96 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C11H18FNO4Na: 270.1118; found: 270.1116.
#
Methyl (Z)-5-(tert-Butoxycarbonylamino)-4-fluoro-6-(4-methoxybenzyloxy)hex-3-enoate (19l)
Yield: 0.25 g (27%, 0.62 mmol); yellow oil.
IR (neat): 3359, 2977, 1741, 1713, 1613, 1586, 1514, 1458, 1391, 1366, 1249, 1172, 1101, 1034, 949, 821, 491 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.44 (9 H, s), 3.16–3.18 (2 H, m), 3.54 (1 H, dd, J = 4.62, 9.70 Hz), 3.61–3.64 (1 H, m), 3.68 (3 H, s), 3.80 (3 H, s), 4.42 (1 H, br s), 4.46 (2 H, s), 5.00–5.11 (1 H, m), 5.10 (1 H, dt, J = 36.23, 6.99 Hz), 6.85–6.89 (2 H, m), 7.21–7.24 (2 H, m).
13C NMR (100 MHz, CDCl3): δ = 28.4, 29.3 (d, J = 5.8 Hz), 51.2 (d, J = 31.7 Hz), 52.1, 55.4, 68.8, 73.0, 80.1, 99.2 (d, J = 12.4 Hz), 113.9, 129.4, 129.8, 155.1, 158.2 (d, J = 257.9 Hz), 159.4, 171.5 (d, J = 1.2 Hz).
19F NMR (376 MHz, CDCl3): δ = –117.61 (1 F, dd, J = 8.98, 36.23 Hz).
HRMS (FAB+): m/z [M + Na]+ calcd for C20H28FNO6Na: 420.1798; found: 420.1795.
#
#
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org.accesdistant.sorbonne-universite.fr/10.1055/s-0035-1560390.
- Supporting Information
-
References
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- 1b Yanai H, Taguchi T. Eur. J. Org. Chem. 2011; 5939
- 1c Couve-Bonnaire S, Cahard D, Pannecoucke X. Org. Biomol. Chem. 2007; 5: 1151
- 1d Zhao K, Lim DS, Funaki T, Welch JT. Bioorg. Med. Chem. 2003; 11: 207
- 2a Yang M.-H, Matikonda SS, Altman RA. Org. Lett. 2013; 15: 3894
- 2b Greedy B, Gouverneur V. Chem. Commun. 2001; 233
- 2c Tius MA, Kawakami JK. Tetrahedron 1995; 51: 3997
- 2d Lee SH, Schwartz J. J. Am. Chem. Soc. 1986; 108: 2445
- 3a Pfund E, Masson S, Vazeux M, Lequeux T. J. Org. Chem. 2004; 69: 4670
- 3b van Steenis JH, van der Gen A. Eur. J. Org. Chem. 2001; 897
- 3c Tsai H.-J. Tetrahedron Lett. 1996; 37: 629
- 4a Nakamura Y, Okada M, Sato A, Horikawa H, Koura M, Saito A, Taguchi T. Tetrahedron 2005; 61: 5741
- 4b Otaka A, Watanabe J, Yukimasa A, Sasaki Y, Watanabe H, Kinoshita T, Oishi S, Tamamura H, Fujii N. J. Org. Chem. 2004; 69: 1634
- 4c Otaka A, Watanabe H, Yukimasa A, Oishi S, Tamamura H, Fujii N. Tetrahedron Lett. 2001; 42: 5443
- 5a Cao C.-R, Ou S, Jiang M, Liu J.-T. Org. Biomol. Chem. 2014; 12: 467
- 5b Larnaud F, Pfund E, Linclau B, Lequeux T. Tetrahedron 2014; 70: 5632
- 5c Yan X.-W, Zhang Q, Wei W, Ji J.-X. Tetrahedron Lett. 2014; 55: 3750
- 5d Prakash GK. S, Zhang Z, Wang F, Rahm M, Ni C, Iuliucci M, Haiges R, Olah GA. Chem. Eur. J. 2014; 20: 831
- 5e Schneider C, Masi D, Couve-Bonnaire S, Pannecoucke X, Hoarau C. Angew. Chem. Int. Ed. 2013; 52: 3246
- 5f Macé A, Tripoteau F, Zhao Q, Gayon E, Vrancken E, Campagne J.-M, Carboni B. Org. Lett. 2013; 15: 906
- 5g Kajjout M, Smietana M, Leroy J, Rolando C. Tetrahedron Lett. 2013; 54: 1658
- 5h Lecea M, Grassin A, Ferreiro-Mederos L, Choppin S, Urbano A, Carreňo MC, Colobert F. Eur. J. Org. Chem. 2013; 4486
- 5i Bergeron M, Guyader D, Paquin J.-F. Org. Lett. 2012; 14: 5888
- 5j Yanai H, Okada H, Sato A, Okada M, Taguchi T. Tetrahedron Lett. 2011; 52: 2997
- 5k Bergeron M, Johnson T, Paquin J.-F. Angew. Chem. Int. Ed. 2011; 50: 11112
- 5l Nikolova GS, Haufe G. Beilstein J. Org. Chem. 2008; 4: 12
- 5m Ghosh AK, Zajc B. Org. Lett. 2006; 8: 1553
- 5n Saito A, Nakagawa M, Taguchi T. J. Fluorine Chem. 2005; 126: 1166
- 5o Wang Z, Gonzalez A, Wnuk SF. Tetrahedron Lett. 2005; 46: 5313
- 5p Nakagawa M, Saito A, Soga A, Yamamoto N, Taguchi T. Tetrahedron Lett. 2005; 46: 5257
- 5q Dutheuil G, Lei X, Pannecoucke X, Quirion J.-C. J. Org. Chem. 2005; 70: 1911
- 5r Nakamura Y, Okada M, Horikawa H, Taguchi T. J. Fluorine Chem. 2002; 117: 143
- 5s Shimizu M, Hata T, Hiyama T. Tetrahedron Lett. 1999; 40: 7375
- 5t Chen C, Wilcoxen K, Kim K, McCarthy JR. Tetrahedron Lett. 1997; 38: 7677
- 5u Allmendinger T, Felder E, Hungarbühler E. Tetrahedron Lett. 1990; 31: 7301
- 6a Kuehnel MF, Holstein P, Kliche M, Krüger J, Matthies S, Nitsch D, Schutt J, Sparenberg M, Lentz D. Chem. Eur. J. 2012; 18: 10701
- 6b Clot E, Eisenstein O, Jasim N, Macgregor SA, Mcgrady JE, Perutz RN. Acc. Chem. Res. 2011; 44: 333
- 6c Amii H, Uneyama K. Chem. Rev. 2009; 109: 2119
- 6d Ohashi M, Shibata M, Saijo H, Kambara T, Ogoshi S. Organometallics 2013; 32: 3631
- 6e Lv H, Cai Y.-B, Zhang JL. Angew. Chem. Int. Ed. 2013; 52: 1
- 6f Guo W.-J, Wang Z.-X. J. Org. Chem. 2013; 78: 1054
- 6g Yu D, Shen Q, Lu L. J. Org. Chem. 2012; 77: 1798
- 6h Ohashi M, Kambara T, Hatanaka T, Saijo H, Doi R, Ogoshi S. J. Am. Chem. Soc. 2011; 133: 3256
- 6i Schaub T, Backes M, Radius U. J. Am. Chem. Soc. 2006; 128: 15964
- 7a Takai K. Org. React. 2004; 64: 253
- 7b Jin H, Uenishi J, Christ WJ, Kishi Y. J. Am. Chem. Soc. 1986; 108: 5644
- 7c Takai K, Kimura K, Kuroda T, Hiyama T, Nozaki H. Tetrahedron Lett. 1983; 24: 5281
- 8 Nihei T, Yokotani S, Ishihara T, Konno T. Chem. Commun. 2014; 50: 1543
- 9 Shimada T, Konno T, Ishihara T. Chem. Lett. 2007; 36: 636
- 10 For the preparation of 3, see: Peng S, Qing F.-L, Li Y.-Q, Hu C.-M. J. Org. Chem. 2000; 65: 694
- 11a Sasaki Y, Hosono E. Jpn Kokai Tokkyo Koho 04091051, 1992
- 11b Chen J, Hu C.-M. J. Chem. Soc., Perkin Trans. 1 1994; 1111
- 12a Bartberger MD, Dolbier WR. Jr, Lusztyk J, Ingold KU. Tetrahedron 1997; 53: 9857
- 12b Gonzalez J, Foti CJ, Elsheimer S. J. Org. Chem. 1991; 56: 4322
- 13 It has been discussed that LiI plays an important role in the solubility of CrCl2 in DMF, see: Wessjohann W, Gabriel T. J. Org. Chem. 1997; 62: 3772
- 14 The stereochemical assignments of 9, 10, 12, and 14 were done based on the analyses of 1H NMR spectra. The coupling constants between vinyl H and F were 21–23 Hz for 9 and 35–38 Hz for 10, 12, and 14, which indicate that 9 and 10, 12, 14 possess E- and Z-configuration, respectively. The details are given in the Supporting Information.
- 15 When the reaction was carried out at –40 °C for 16 h in the presence of 2.0 equiv of Ti(Oi-Pr)4, instead of a catalytic amount of LiI, 13 was obtained in 40% yield.
- 16 We first attempted the nucleophilic substitution reaction of NaN3 with 10a under the same conditions as described in Table 5. However, no deisred adduct was detected.
- 17 Watanabe D, Koura M, Saito A, Yanai H, Nakamura Y, Okada M, Sato A, Taguchi T. J. Fluorine Chem. 2011; 132: 327
- 18a Baati R, Barma DK, Krishna UM, Mioskowski C, Falck JR. Tetrahedron Lett. 2002; 43: 959
- 18b Baati R, Barma DK, Falck JR, Mioskowski C. J. Am. Chem. Soc. 2001; 123: 9196
- 18c Barma DK, Baati R, Valleix A, Mioskowski C, Falck JR. Org. Lett. 2001; 3: 4237
- 19 Pitterna T, Böger M, Maienfisch P. Chimia 2004; 58: 108
- 20 Known compounds, see ref. 5n and 5q.
For reviews, see:
For recent studies, see:
For Cr(II)-mediated reactions, see:
It has been reported that trichloroalkanes in the presence of 4.0 equiv of CrCl2 can be converted into the corresponding chlorovinylidene chromium(III) carbenoids, see:
-
References
- 1a Chang W, Mosley RT, Bansal S, Keilman M, Lam AM, Furman PA, Otto MJ, Sofia MJ. Bioorg. Med. Chem. Lett. 2012; 22: 2938
- 1b Yanai H, Taguchi T. Eur. J. Org. Chem. 2011; 5939
- 1c Couve-Bonnaire S, Cahard D, Pannecoucke X. Org. Biomol. Chem. 2007; 5: 1151
- 1d Zhao K, Lim DS, Funaki T, Welch JT. Bioorg. Med. Chem. 2003; 11: 207
- 2a Yang M.-H, Matikonda SS, Altman RA. Org. Lett. 2013; 15: 3894
- 2b Greedy B, Gouverneur V. Chem. Commun. 2001; 233
- 2c Tius MA, Kawakami JK. Tetrahedron 1995; 51: 3997
- 2d Lee SH, Schwartz J. J. Am. Chem. Soc. 1986; 108: 2445
- 3a Pfund E, Masson S, Vazeux M, Lequeux T. J. Org. Chem. 2004; 69: 4670
- 3b van Steenis JH, van der Gen A. Eur. J. Org. Chem. 2001; 897
- 3c Tsai H.-J. Tetrahedron Lett. 1996; 37: 629
- 4a Nakamura Y, Okada M, Sato A, Horikawa H, Koura M, Saito A, Taguchi T. Tetrahedron 2005; 61: 5741
- 4b Otaka A, Watanabe J, Yukimasa A, Sasaki Y, Watanabe H, Kinoshita T, Oishi S, Tamamura H, Fujii N. J. Org. Chem. 2004; 69: 1634
- 4c Otaka A, Watanabe H, Yukimasa A, Oishi S, Tamamura H, Fujii N. Tetrahedron Lett. 2001; 42: 5443
- 5a Cao C.-R, Ou S, Jiang M, Liu J.-T. Org. Biomol. Chem. 2014; 12: 467
- 5b Larnaud F, Pfund E, Linclau B, Lequeux T. Tetrahedron 2014; 70: 5632
- 5c Yan X.-W, Zhang Q, Wei W, Ji J.-X. Tetrahedron Lett. 2014; 55: 3750
- 5d Prakash GK. S, Zhang Z, Wang F, Rahm M, Ni C, Iuliucci M, Haiges R, Olah GA. Chem. Eur. J. 2014; 20: 831
- 5e Schneider C, Masi D, Couve-Bonnaire S, Pannecoucke X, Hoarau C. Angew. Chem. Int. Ed. 2013; 52: 3246
- 5f Macé A, Tripoteau F, Zhao Q, Gayon E, Vrancken E, Campagne J.-M, Carboni B. Org. Lett. 2013; 15: 906
- 5g Kajjout M, Smietana M, Leroy J, Rolando C. Tetrahedron Lett. 2013; 54: 1658
- 5h Lecea M, Grassin A, Ferreiro-Mederos L, Choppin S, Urbano A, Carreňo MC, Colobert F. Eur. J. Org. Chem. 2013; 4486
- 5i Bergeron M, Guyader D, Paquin J.-F. Org. Lett. 2012; 14: 5888
- 5j Yanai H, Okada H, Sato A, Okada M, Taguchi T. Tetrahedron Lett. 2011; 52: 2997
- 5k Bergeron M, Johnson T, Paquin J.-F. Angew. Chem. Int. Ed. 2011; 50: 11112
- 5l Nikolova GS, Haufe G. Beilstein J. Org. Chem. 2008; 4: 12
- 5m Ghosh AK, Zajc B. Org. Lett. 2006; 8: 1553
- 5n Saito A, Nakagawa M, Taguchi T. J. Fluorine Chem. 2005; 126: 1166
- 5o Wang Z, Gonzalez A, Wnuk SF. Tetrahedron Lett. 2005; 46: 5313
- 5p Nakagawa M, Saito A, Soga A, Yamamoto N, Taguchi T. Tetrahedron Lett. 2005; 46: 5257
- 5q Dutheuil G, Lei X, Pannecoucke X, Quirion J.-C. J. Org. Chem. 2005; 70: 1911
- 5r Nakamura Y, Okada M, Horikawa H, Taguchi T. J. Fluorine Chem. 2002; 117: 143
- 5s Shimizu M, Hata T, Hiyama T. Tetrahedron Lett. 1999; 40: 7375
- 5t Chen C, Wilcoxen K, Kim K, McCarthy JR. Tetrahedron Lett. 1997; 38: 7677
- 5u Allmendinger T, Felder E, Hungarbühler E. Tetrahedron Lett. 1990; 31: 7301
- 6a Kuehnel MF, Holstein P, Kliche M, Krüger J, Matthies S, Nitsch D, Schutt J, Sparenberg M, Lentz D. Chem. Eur. J. 2012; 18: 10701
- 6b Clot E, Eisenstein O, Jasim N, Macgregor SA, Mcgrady JE, Perutz RN. Acc. Chem. Res. 2011; 44: 333
- 6c Amii H, Uneyama K. Chem. Rev. 2009; 109: 2119
- 6d Ohashi M, Shibata M, Saijo H, Kambara T, Ogoshi S. Organometallics 2013; 32: 3631
- 6e Lv H, Cai Y.-B, Zhang JL. Angew. Chem. Int. Ed. 2013; 52: 1
- 6f Guo W.-J, Wang Z.-X. J. Org. Chem. 2013; 78: 1054
- 6g Yu D, Shen Q, Lu L. J. Org. Chem. 2012; 77: 1798
- 6h Ohashi M, Kambara T, Hatanaka T, Saijo H, Doi R, Ogoshi S. J. Am. Chem. Soc. 2011; 133: 3256
- 6i Schaub T, Backes M, Radius U. J. Am. Chem. Soc. 2006; 128: 15964
- 7a Takai K. Org. React. 2004; 64: 253
- 7b Jin H, Uenishi J, Christ WJ, Kishi Y. J. Am. Chem. Soc. 1986; 108: 5644
- 7c Takai K, Kimura K, Kuroda T, Hiyama T, Nozaki H. Tetrahedron Lett. 1983; 24: 5281
- 8 Nihei T, Yokotani S, Ishihara T, Konno T. Chem. Commun. 2014; 50: 1543
- 9 Shimada T, Konno T, Ishihara T. Chem. Lett. 2007; 36: 636
- 10 For the preparation of 3, see: Peng S, Qing F.-L, Li Y.-Q, Hu C.-M. J. Org. Chem. 2000; 65: 694
- 11a Sasaki Y, Hosono E. Jpn Kokai Tokkyo Koho 04091051, 1992
- 11b Chen J, Hu C.-M. J. Chem. Soc., Perkin Trans. 1 1994; 1111
- 12a Bartberger MD, Dolbier WR. Jr, Lusztyk J, Ingold KU. Tetrahedron 1997; 53: 9857
- 12b Gonzalez J, Foti CJ, Elsheimer S. J. Org. Chem. 1991; 56: 4322
- 13 It has been discussed that LiI plays an important role in the solubility of CrCl2 in DMF, see: Wessjohann W, Gabriel T. J. Org. Chem. 1997; 62: 3772
- 14 The stereochemical assignments of 9, 10, 12, and 14 were done based on the analyses of 1H NMR spectra. The coupling constants between vinyl H and F were 21–23 Hz for 9 and 35–38 Hz for 10, 12, and 14, which indicate that 9 and 10, 12, 14 possess E- and Z-configuration, respectively. The details are given in the Supporting Information.
- 15 When the reaction was carried out at –40 °C for 16 h in the presence of 2.0 equiv of Ti(Oi-Pr)4, instead of a catalytic amount of LiI, 13 was obtained in 40% yield.
- 16 We first attempted the nucleophilic substitution reaction of NaN3 with 10a under the same conditions as described in Table 5. However, no deisred adduct was detected.
- 17 Watanabe D, Koura M, Saito A, Yanai H, Nakamura Y, Okada M, Sato A, Taguchi T. J. Fluorine Chem. 2011; 132: 327
- 18a Baati R, Barma DK, Krishna UM, Mioskowski C, Falck JR. Tetrahedron Lett. 2002; 43: 959
- 18b Baati R, Barma DK, Falck JR, Mioskowski C. J. Am. Chem. Soc. 2001; 123: 9196
- 18c Barma DK, Baati R, Valleix A, Mioskowski C, Falck JR. Org. Lett. 2001; 3: 4237
- 19 Pitterna T, Böger M, Maienfisch P. Chimia 2004; 58: 108
- 20 Known compounds, see ref. 5n and 5q.
For reviews, see:
For recent studies, see:
For Cr(II)-mediated reactions, see:
It has been reported that trichloroalkanes in the presence of 4.0 equiv of CrCl2 can be converted into the corresponding chlorovinylidene chromium(III) carbenoids, see:
